Collagen

Collagen

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Collagen ˈkɒlədʒɨn is a group of naturally occurring protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s found in animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...

s, especially in the flesh and connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

s of mammals. It is the main component of connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content. Collagen, in the form of elongated fibril
Fibril
Fibril is a fine fiber approximately 1 nm in diameter.Cytoplasmic fibrils are observed on the protoplasmic cylinders found in most spirochetal species, although no function of the cytoplasmic fibrils has been ascribed....

s, is mostly found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc. The fibroblast is the most common cell which creates collagen.

In muscle tissue, it serves as a major component of the endomysium
Endomysium
The endomysium, meaning within the muscle, is a layer of connective tissue that ensheaths a muscle fiber and is composed mostly from reticular fibers. It also contains capillaries, nerves, and lymphatics...

. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles. Gelatin
Gelatin
Gelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...

, which is used in food and industry, is collagen that has been irreversibly hydrolyzed.

History and background


The molecular and packing structures of collagen have eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s. Since that time, many prominent scholars, including Nobel laureates Crick
Francis Crick
Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson...

, Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...

, Rich
Alexander Rich
Alexander Rich, MD is a biologist and biophysicist. He is the William Thompson Sedgwick Professor of Biophysics at MIT and Harvard Medical School. Dr. Rich earned both an A.B. and an M.D. from Harvard University. He was a post-doc of Linus Pauling along with James Watson...

 and Yonath
Ada Yonath
Ada E. Yonath is an Israeli crystallographer best known for her pioneering work on the structure of the ribosome. She is the current director of the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly of the Weizmann Institute of Science. In 2009, she received the Nobel...

, and others, including Brodsky, Berman
Helen M. Berman
Helen M. Berman is the director of the – one of the member organizations of the Worldwide Protein Data Bank and a Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University. A structural biologist, her work includes structural analysis of protein-nucleic acid complexes,...

, and Ramachandran
Gopalasamudram Narayana Iyer Ramachandran
Gopalasamudram Narayana Iyer Ramachandran, or G.N. Ramachandran, was a prominent Indian scientist, best known for his work that led to his creation of the Ramachandran plot for understanding peptide structure. He was the first to propose a triple-helical model for the structure of collagen...

, concentrated on the conformation of the collagen monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...

. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical "Madras" model, which provided an essentially correct model of the molecule's quaternary structure
Quaternary structure
In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...

  although this model still required some refinement. The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal ...or quasi-hexagonal. As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibril
Microfibril
The microfibril is a very fine fibril, or fiber-like strand, consisting of glycoproteins and cellulose. It is usually, but not always, used as a general term in describing the structure of protein fiber, examples are hair and sperm tail. Its most frequently observed structural pattern is 9+2...

lar. The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy. In 2006, the microfibrillar structure of adult tendon, as described by Fraser, Miller, and Wess (amongst others), was confirmed as being closest to the observed structure, although it oversimplified the topological progression of neighboring collagen molecules, and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril. Various cross linking agents like dopaquinone, embelin, potassium embelate and 5-O-methyl embelin could be developed as potential
cross-linking/stabilization agent of collagen preparation and its application as wound dressing
sheet in clinical applications is enhanced.

Chemistry of Collagen


Collagen is a composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2). The amino acid composition of collagen is atypical for proteins, particularly with respect to its high hydroxyproline content. The most common motifs in the amino acid sequence of collagen are Glycine-Proline-X and Glycine-X-Hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline. The average amino acid composition for fish and mammal skin is given.
Amino Acid Abundance in Mammal Skin (Residues/1000) Abundance in Fish Skin (Residues/1000)
Asp
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...

 
47 47
Hyp
Hydroxyproline
-4-Hydroxyproline, or L-hydroxyproline , is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank.-Structure and discovery:...

 
95 67
Thr
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...

 
19 26
Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

 
36 46
Glu
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

 
74 76
Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

 
126 108
Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

 
329 339
Ala
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...

 
109 114
Val
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...

 
22 21
Met
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 
6 13
Ile
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....

 
11 11
Leu
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...

 
24 23
Tyr
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 
3 3
Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...

 
13 14
Hyl
Hydroxylysine
5-Hydroxylysine is an amino acid with the molecular formula C6H14N2O3. It was first discovered in 1921 by Donald Van Slyke. It is a hydroxy derivative of lysine. It is most widely known as a component of collagen....

 
6 8
Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 
29 26
His
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 
5 7
Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

 
49 52

Synthesis of Collagen


The synthesis of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems is the other form of collagen. It should be noted that all types of collagens are triple helixes, and the differences lie in the make-up of the alpha peptides created in step 2.
  1. Transcription of mRNA: There are approximately 34 genes associated with collagen formation, each coding for a specific mRNA sequence, and typically have the "COL" prefix. The beginning of collagen synthesis begins with turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).
  2. Pre-pro-peptide Formation: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm it links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is known as the signal sequence. The signal sequence on the N-terminal of the peptide is recognized by a signal recognition particle
    Signal recognition particle
    The signal recognition particle is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes....

     on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the endoplasmic reticulum for post-translational processing. Note that it is not known as pre-pro-collagen.
  3. Alpha Peptide to Procollagen: Three modifications of the pre-pro-peptide occurs leading to the formation of the alpha peptide. Secondly, the triple helix known as procollagen is formed before being transported in a transport vesicle to the golgi apparatus. 1) The signal peptide on the N-terminal is dissolved, and the molecule is now known as propeptide (not procollagen). 2) Hydroxylation of lysines and prolines on propeptide by the enzymes prolyl hydroxylase and lysyl hydroxylase (to produce hydroxyproline and hydroxylysine) occurs to aid crosslinking of the alpha peptides. It is this enzymatic step that requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by 3 alpha peptides). 3) Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxy groups that were placed onto lysines, but not on prolines. From here the hydroxylated and glycosylated propeptide twists towards the left very tightly and then three propeptides will form a triple helix. It is important to remember that this molecule, now known as procollagen (not propeptide) is composed of a twisted portion (center) and two loose ends on either end. At this point the procollagen is packaged into a transfer vesicle destined for the golgi apparatus.
  4. Golgi Apparatus Modification: In the golgi apparatus, the procollagen goes through one last post-translational modification before being secreted out of the cell. In this step oligosaacharides (not monosaacharides like in step 3) are added, and then the alpha peptide is packaged into a secretory vesicle destined for the extracellular space.
  5. Formation of Tropocollagen: Once outside the cell, membrane bound enzymes known as collagen peptidases, remove the "loose ends" of the procollagen molecule. What is left is known as tropocollagen. Defect in this step produces one of the many collagenopathies known as Ehlers-danlos syndrome
    Ehlers-Danlos syndrome
    Ehlers–Danlos syndrome is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen . The collagen in connective tissue helps tissues to resist deformation...

    .This step is absent when synthesizing type IV or meshwork collagen.
  6. Formation of the Collagen Fibril: Lysyl oxidase and extracellular enzyme produces the final step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.

Molecular structure


The tropocollagen or collagen molecule is a subunit of larger collagen aggregates such as fibrils. At approximately 300 nm long and 1.5 nm in diameter, it is made up of three polypeptide strands (called alpha peptides, see step 2), each possessing the conformation of a left-handed helix
Helix
A helix is a type of smooth space curve, i.e. a curve in three-dimensional space. It has the property that the tangent line at any point makes a constant angle with a fixed line called the axis. Examples of helixes are coil springs and the handrails of spiral staircases. A "filled-in" helix – for...

 (its name is not to be confused with the commonly occurring alpha helix, a right-handed structure). These three left-handed helices are twisted together into a right-handed coiled coil
Coiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...

, a triple helix or "super helix", a cooperative quaternary structure
Quaternary structure
In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...

 stabilized by numerous hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

s. With type I collagen and possibly all fibrillar collagens if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.

A distinctive feature of collagen is the regular arrangement of amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

-Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

-X or Gly-X-Hyp
Hydroxyproline
-4-Hydroxyproline, or L-hydroxyproline , is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank.-Structure and discovery:...

, where X may be any of various other amino acid residues. Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2 character of collagen alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk
Silk
Silk is a natural protein fiber, some forms of which can be woven into textiles. The best-known type of silk is obtained from the cocoons of the larvae of the mulberry silkworm Bombyx mori reared in captivity...

 fibroin
Fibroin
Fibroin is a type of protein created by Bombyx mori in the production of silk. Silk emitted by the silkworm consists of two main proteins, sericin and fibroin, fibroin being the structural center of the silk, and sericin being the sticky material surrounding it.The fibroin protein consists of...

. About 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

, and elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...

 is rich in glycine, proline, and alanine (Ala), whose side group
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

 is a small, inert methyl group. Such high glycine and regular repetitions are never found in globular proteins save for very short sections of their sequence. Chemically-reactive
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

 side groups are not needed in structural proteins, as they are in enzymes and transport proteins; however, collagen is not quite just a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its nonproline-rich regions have cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.

Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...

, whose body temperatures
Thermoregulation
Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different...

 are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals. The lower proline and hydroxproline contents of cold-water fish and other poikilotherm animals leads to their collagen having a lower thermal stability than mammalian collagen. This lower thermal stability means that gelatin
Gelatin
Gelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...

 derived from fish collagen is not suitable for many Gelatin.

The tropocollagen subunits
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...

 spontaneously self-assemble
Molecular self-assembly
Molecular self-assembly is the process by which molecules adopt a defined arrangement without guidance or management from an outside source. There are two types of self-assembly, intramolecular self-assembly and intermolecular self-assembly...

, with regularly staggered ends, into even larger arrays in the extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...

 spaces of tissues. In the fibrillar collagens, the molecules are staggered from each other by about 67 nm
Nanometre
A nanometre is a unit of length in the metric system, equal to one billionth of a metre. The name combines the SI prefix nano- with the parent unit name metre .The nanometre is often used to express dimensions on the atomic scale: the diameter...

 (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains four plus a fraction collagen molecules, because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore, in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the “overlap”, and a part containing only four molecules, called the "gap". The triple-helices are also arranged in a hexagonal or quasihexagonal array in cross-section, in both the gap and overlap regions.

There is some covalent
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....

 crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils). Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players. Collagen's insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked
Cross-link
Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers . When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of...

. However, advances in microscopy techniques electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to better understanding the way in which collagen structure affects cell-cell and cell-matrix communication, and how tissues are constructed in growth and repair, and changed in development and disease. For example using AFM –based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.

Collagen fibrils are semicrystalline aggregates of collagen molecules. Collagen fibers are bundles of fibrils.

Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. Forty nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite
Hydroxylapatite
Hydroxylapatite, also called hydroxyapatite , is a naturally occurring mineral form of calcium apatite with the formula Ca53, but is usually written Ca1062 to denote that the crystal unit cell comprises two entities. Hydroxylapatite is the hydroxyl endmember of the complex apatite group...

, Ca10(PO4)6(OH)2 with some phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

. It is in this way that certain kinds of cartilage turn into bone. Type I collagen gives bone its tensile strength.

Types and associated disorders


Collagen occurs in many places throughout the body. Over 90% of the collagen in the body, however, is of type one.

So far, 28 types of collagen have been identified and described. The five most common types are:
  • Collagen I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)
  • Collagen II: cartilage (main component of cartilage)
  • Collagen III: reticulate (main component of reticular fibers), commonly found alongside type I.
  • Collagen IV: forms bases of cell basement membrane
  • Collagen V: cells surfaces, hair and placenta


Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.
Type Notes Gene(s) Disorders
Collagen disease
Collagen disease is a term previously used to describe systemic autoimmune diseases , but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue.The term "collagen disease" was coined by Dr...


>-
| I
Type-I collagen
Type-I collagen is the most abundant collagen of the human body.It is present in scar tissue, the end product when tissue heals by repair.It is found in tendons, the endomysium of myofibrils and the organic part of bone.- See also :* Collagen...

 
This is the most abundant collagen of the human body. It is present in scar tissue
Scar
Scars are areas of fibrous tissue that replace normal skin after injury. A scar results from the biological process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in...

, the end product when tissue heals
Healing
Physiological healing is the restoration of damaged living tissue, organs and biological system to normal function. It is the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area....

 by repair. It is found in tendon
Tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...

s, skin, artery walls, the endomysium
Endomysium
The endomysium, meaning within the muscle, is a layer of connective tissue that ensheaths a muscle fiber and is composed mostly from reticular fibers. It also contains capillaries, nerves, and lymphatics...

 of myofibrils, fibrocartilage, and the organic part of bones and teeth.
COL1A1
COL1A1
Collagen, type I, alpha 1, also known as COL1A1, is a human gene that encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including cartilage....

, COL1A2
COL1A2
Collagen alpha-2 chain is a protein that in humans is encoded by the COL1A2 gene.-External links:* -Further reading:...

 
osteogenesis imperfecta
Osteogenesis imperfecta
Osteogenesis imperfecta is a genetic bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen...

, Ehlers–Danlos syndrome, Infantile cortical hyperostosis
Infantile cortical hyperostosis
Infantile cortical hyperostosis is a self-limited inflammatory disorder of infants that causes bone changes, soft tissue swelling and irritability. The disease may be present at birth or occur shortly thereafter. The cause is unknown. Both familial and sporadic forms occur...

 aka Caffey's disease
>-
| II
Type-II collagen
Type-II collagen is the basis for articular cartilage and hyaline cartilage.It makes up 50% of all protein in cartilage and 85-90% of collagen of articular cartilage....

 
Hyaline cartilage
Hyaline cartilage
Hyaline cartilage consists of a slimy mass, pearly bluish in colour with firm consistency and considerable collagen. It contains no nerves or blood vessels, and its structure is relatively simple....

, makes up 50% of all cartilage protein. Vitreous humour
Vitreous humour
The vitreous humour or vitreous humor is the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates...

 of the eye.
COL2A1
COL2A1
Collagen, type II, alpha 1 , also known as COL2A1, is a human gene that provides instructions for the production of the pro-alpha1 chain of type II collagen....

 
Collagenopathy, types II and XI
Collagenopathy, types II and XI
The type II and XI collagenopathies are a group of disorders that affect connective tissue, the tissue that supports the body's joints and organs. These disorders are caused by defects in type II or type XI collagen. Collagens are complex molecules that provide structure, strength, and elasticity ...


>-
| III
Type-III collagen
Collagen alpha-1 chain is a protein that in humans is encoded by the COL3A1 gene, which is located on chromosome 2.- Function :Collagen alpha-1 chain is a fibrillar collagen that is found in extensible connective tissues such as skin, lung, and the vascular system, frequently in association with...

 
This is the collagen of granulation tissue
Granulation tissue
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...

, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Reticular fiber
Reticular fiber
Reticular fibers or reticulin is a histological term used to describe a type of fiber in connective tissue composed of type III collagen. Reticular fibers crosslink to form a fine meshwork...

. Also found in artery walls, skin, intestines and the uterus
COL3A1  Dupuytren's contracture
Dupuytren's contracture
Dupuytren's contracture , is a fixed flexion contracture of the hand where the fingers bend towards the palm and cannot be fully extended...


>-
| IV
Type-IV collagen
Type-IV collagen is a type of collagen found primarily in the basal lamina. The type IV collagen C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, type-IV lacks the regular glycine in every third residue...

 
basal lamina
Basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....

; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....

 in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

.
COL4A1
COL4A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL4A1 gene.Mutations in COL4A1 exons 24 and 25 are associated with HANAC ....

, COL4A2
COL4A2
Collagen alpha-2 chain is a protein that in humans is encoded by the COL4A2 gene.-Further reading:...

, COL4A3
COL4A3
Collagen alpha-3 chain is a protein that in humans is encoded by the COL4A3 gene.-Further reading:...

, COL4A4
COL4A4
Collagen alpha-4 chain is a protein that in humans is encoded by the COL4A4 gene.-Further reading:...

, COL4A5
COL4A5
Collagen alpha-5 chain is a protein that in humans is encoded by the COL4A5 gene.-Disease Database:-Further reading:...

, COL4A6
COL4A6
Collagen alpha-6 chain is a protein that in humans is encoded by the COL4A6 gene.-Further reading:...

 
Alport syndrome
Alport syndrome
Alport syndrome or hereditary nephritis is a genetic disorder characterized by glomerulonephritis, endstage kidney disease, and hearing loss. Alport syndrome can also affect the eyes . The presence of blood in the urine is almost always found in this condition.It was first identified in a British...

, Goodpasture's syndrome
Goodpasture's syndrome
Goodpasture’s syndrome is a rare disease characterized by glomerulonephritis and hemorrhaging of the lungs...


>-
| V
most interstitial tissue, assoc. with type I, associated with placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

 
COL5A1
COL5A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL5A1 gene.-External links:*...

, COL5A2
COL5A2
Collagen alpha-2 chain is a protein that in humans is encoded by the COL5A2 gene.-External links:*...

, COL5A3
COL5A3
Collagen alpha-3 chain is a protein that in humans is encoded by the COL5A3 gene.-Further reading:...

 
>-
| VI
most interstitial tissue, assoc. with type I COL6A1
COL6A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL6A1 gene.- Function :The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common...

, COL6A2
COL6A2
Collagen alpha-2 chain is a protein that in humans is encoded by the COL6A2 gene.- Function :This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand...

, COL6A3
COL6A3
Collagen alpha-3 chain is a protein that in humans is encoded by the COL6A3 gene.- Function :This gene encodes the alpha 3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha 3 chain of type VI collagen is much larger than...

 
Bethlem myopathy
Bethlem myopathy
Bethlem myopathy is an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy, that is caused by a variation in one of the three genes coding for type VI collagen...


>-
| VII
forms anchoring fibrils in dermal epidermal junctions COL7A1
COL7A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL7A1 gene.- Function :This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous...

 
epidermolysis bullosa dystrophica
Epidermolysis bullosa dystrophica
Epidermolysis bullosa dystrophica or Dystrophic EB is an inherited disease affecting the skin and other organs. "Butterfly children" is the term given to those born with the disease, as their skin is seen to be as delicate and fragile as that of a butterfly.-Causes:DEB is caused by genetic defects...


>-
| VIII
some endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 cells
COL8A1
COL8A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL8A1 gene.-Further reading:...

, COL8A2
COL8A2
Collagen alpha-2 chain is a protein that in humans is encoded by the COL8A2 gene. Mutations of the gene are linked to posterior polymorphous dystrophy type 2.-Further reading:...

 
Posterior polymorphous corneal dystrophy 2
Posterior polymorphous corneal dystrophy 2
Posterior Polymorphous Corneal Dystrophy 2 is a rare disease of the cornea. It is linked to the mutations in COL8A2.-See also:*Posterior polymorphous corneal dystrophy 1*Posterior polymorphous corneal dystrophy 3-External links:...


>-
| IX
FACIT collagen
FACIT collagen
FACIT collagen refers to a type of collagen which is also a proteoglycan.FACIT collagens include collagen types IX, XII, XIV, XIX, and XXI.COL22A1 is also included in this class....

, cartilage, assoc. with type II and XI fibrils
COL9A1
COL9A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL9A1 gene.-External Links:* * -Further reading:...

, COL9A2
COL9A2
Collagen alpha-2 chain is a protein that in humans is encoded by the COL9A2 gene.-External links:* -Further reading:...

, COL9A3
COL9A3
Collagen alpha-3 chain is a protein that in humans is encoded by the COL9A3 gene.-External links:* -Further reading:...

 
>-
| X
hypertrophic and mineralizing cartilage COL10A1
COL10A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL10A1 gene.DDR2 is a collagen receptor for it.-Further reading:...

 
>-
| XI
cartilage COL11A1
COL11A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL11A1 gene.- Function :The COL11A1 gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1...

, COL11A2
COL11A2
COL11A2 is a human gene that is one of several genes that provide instructions for the production of type XI collagen. The COL11A2 gene produces one component of this type of collagen, called the pro-alpha2 chain...

 
Collagenopathy, types II and XI
Collagenopathy, types II and XI
The type II and XI collagenopathies are a group of disorders that affect connective tissue, the tissue that supports the body's joints and organs. These disorders are caused by defects in type II or type XI collagen. Collagens are complex molecules that provide structure, strength, and elasticity ...


>-
| XII
FACIT collagen
FACIT collagen
FACIT collagen refers to a type of collagen which is also a proteoglycan.FACIT collagens include collagen types IX, XII, XIV, XIX, and XXI.COL22A1 is also included in this class....

, interacts with type I containing fibrils, decorin
Decorin
Decorin is a proteoglycan on average 90 - 140 kilodaltons in size.It belongs to the small leucine-rich proteoglycan family and consists of a protein core containing leucine repeats with a glycosaminoglycan chain consisting of either chondroitin sulfate or dermatan sulfate .Decorin is a small...

 and glycosaminoglycans
COL12A1
COL12A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL12A1 gene.-Further reading:...

 
>-
| XIII
transmembrane collagen, interacts with integrin a1b1, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...

 and components of basement membranes like nidogen and perlecan
Perlecan
Perlecan also known as basement membrane-specific heparan sulfate proteoglycan core protein or heparan sulfate proteoglycan 2 , is a protein that in humans is encoded by the HSPG2 gene....

.
COL13A1
COL13A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL13A1 gene.-Further reading:...

 
>-
| XIV
FACIT collagen
FACIT collagen
FACIT collagen refers to a type of collagen which is also a proteoglycan.FACIT collagens include collagen types IX, XII, XIV, XIX, and XXI.COL22A1 is also included in this class....

 
COL14A1
COL14A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL14A1 gene.-Further reading:...

 
>-
| XV
COL15A1
COL15A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL15A1 gene.-Further reading:...

 
>-
| XVI
COL16A1
COL16A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL16A1 gene.-Further reading:...

 
>-
| XVII
Collagen XVII
Collagen XVII, previously called BP180, is a transmembrane protein which plays a critical role in maintaining the linkage between the intracellular and the extracellular structural elements involved in epidermal adhesion .-Structure:...

 
transmembrane collagen, also known as BP180, a 180 kDa protein COL17A1  Bullous pemphigoid
Bullous pemphigoid
Bullous pemphigoid, also referred to as BP, is an acute or chronic autoimmune skin disease, involving the formation of blisters, more appropriately known as bullae, at the space between the skin layers epidermis and dermis.-Signs and symptoms:...

 and certain forms of junctional epidermolysis bullosa
Epidermolysis bullosa
Epidermolysis bullosa is an inherited connective tissue disease causing blisters in the skin and mucosal membranes, with an incidence of 1/50,000. Its severity ranges from mild to lethal. It is caused by a mutation in the keratin or collagen gene....


>-
| XVIII
Type XVIII collagen
Type XVIII collagen is a type of collagen which can be cleaved to form endostatin....

 
source of endostatin
Endostatin
]Endostatin is a naturally-occurring 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin....

 
COL18A1
COL18A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL18A1 gene.-Further reading:...

 
>-
| XIX
FACIT collagen
FACIT collagen
FACIT collagen refers to a type of collagen which is also a proteoglycan.FACIT collagens include collagen types IX, XII, XIV, XIX, and XXI.COL22A1 is also included in this class....

 
COL19A1
COL19A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL19A1 gene.-Further reading:...

 
>-
| XX
COL20A1
COL20A1
COL20A1 is a collagen gene....

 
>-
| XXI
FACIT collagen
FACIT collagen
FACIT collagen refers to a type of collagen which is also a proteoglycan.FACIT collagens include collagen types IX, XII, XIV, XIX, and XXI.COL22A1 is also included in this class....

 
COL21A1
COL21A1
COL21A1 is a collagen gene....

 
>-
| XXII
COL22A1
COL22A1
COL22A1 is a collagen gene....

 
>-
| XXIII
MACIT collagen – COL23A1
COL23A1
COL23A1 is a collagen gene....

 
>-
| XXIV
COL24A1
COL24A1
COL24A1 is a collagen gene....

 
>-
| XXV
COL25A1
COL25A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL25A1 gene.-Interactions:Collagen, type XXV, alpha 1 has been shown to interact with Amyloid precursor protein.-Further reading:...

 
>-
| XXVI
EMID2
EMID2
Collagen alpha-1 chain is a protein that in humans is encoded by the EMID2 gene.-Further reading:...

 
>-
| XXVII
COL27A1
COL27A1
Collagen alpha-1 chain is a protein that in humans is encoded by the COL27A1 gene.COL27A1 is a type XXVII collagen. It was discovered by James Pace. This gene appears to be turned on in cartilage, the eye, and in the ear...

 
>-
| XXVIII
COL28A1
COL28A1
Collagen, type XXVIII, alpha 1 also known as COL28A1 is a protein that in humans is encoded by the COL28A1 gene. The protein encoded by this gene is a collagen....

 
>-
| XXIX
epidermal collagen COL29A1 Atopic dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...



In addition to the above mentioned disorders, excessive deposition of collagen occurs in scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...

.

Staining


In histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

, collagen is brightly eosinophilic (pink) in standard H&E
H&E stain
H&E stain, HE stain or hematoxylin and eosin stain is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E...

 slides. The dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....

 methyl violet
Methyl violet
Methyl violet is a family of organic compounds that are mainly used as dyes. Depending on the amount of attached methyl groups, the color of the dye can be altered. Its main use is as a purple dye for textiles and to give deep violet colors in paint and ink...

 may be used to stain
Staining (biology)
Staining is an auxiliary technique used in microscopy to enhance contrast in the microscopic image. Stains and dyes are frequently used in biology and medicine to highlight structures in biological tissues for viewing, often with the aid of different microscopes...

 the collagen in tissue samples.

The dye methyl blue
Methyl blue
Methyl blue, also known as Cotton blue, Helvetia blue, Acid blue 93, or C.I. 42780, is a chemical compound with the molecular formula C37H27N3Na2O9S3. It is used as a stain in histology. Methyl blue stains collagen blue in tissue sections. It is soluble in water and slightly soluble in ethanol...

 can also be used to stain collagen and immunohistochemical
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...

 stains are available if required.

The best stain for use in differentiating collagen from other fibers is Masson's trichrome
Masson's trichrome
Masson's trichrome is a three-colour staining protocol used in histology. The recipes evolved from Claude L. Pierre Masson's original formulation to different specific applications, but all are suited for distinguishing cells from surrounding connective tissue....

 stain.

Synthesis



Amino acids


Collagen has an unusual amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 composition and sequence:
  • Glycine
    Glycine
    Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

     (Gly) is found at almost every third residue
    Residue (chemistry)
    In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....

  • Proline
    Proline
    Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

     (Pro) makes up about 17% of collagen
  • Collagen contains two uncommon derivative amino acids not directly inserted during translation
    Translation (genetics)
    In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...

    . These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C
    Vitamin C
    Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

     as a cofactor
    Cofactor (biochemistry)
    A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

    .
    • Hydroxyproline
      Hydroxyproline
      -4-Hydroxyproline, or L-hydroxyproline , is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank.-Structure and discovery:...

       (Hyp), derived from proline.
    • Hydroxylysine
      Hydroxylysine
      5-Hydroxylysine is an amino acid with the molecular formula C6H14N2O3. It was first discovered in 1921 by Donald Van Slyke. It is a hydroxy derivative of lysine. It is most widely known as a component of collagen....

       (Hyl), derived from lysine
      Lysine
      Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

       (Lys). Depending on the type of collagen, varying numbers of hydroxylysines are glycosylated
      Glycosylation
      Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...

       (mostly having disaccharide
      Disaccharide
      A disaccharide or biose is the carbohydrate formed when two monosaccharides undergo a condensation reaction which involves the elimination of a small molecule, such as water, from the functional groups only. Like monosaccharides, disaccharides form an aqueous solution when dissolved in water...

      s attached).


Cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

 stimulates degradation of (skin) collagen into amino acids.

Collagen I formation


Most collagen forms in a similar manner, but the following process is typical for type I:
  1. Inside the cell
    1. Two types of peptide
      Peptide
      Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

       chains are formed during translation
      Translation (genetics)
      In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...

       on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide
      Signal peptide
      A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....

      .
    2. Polypeptide chains are released into the lumen of the RER.
    3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.
    4. Hydroxylation
      Hydroxylation
      Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

       of lysine
      Lysine
      Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

       and proline
      Proline
      Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

       amino acids occurs inside the lumen. This process is dependent on ascorbic acid
      Ascorbic acid
      Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...

       (Vitamin C) as a cofactor
      Cofactor (biochemistry)
      A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

      .
    5. Glycosylation
      Glycosylation
      Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...

       of specific hydroxylysine residues occurs.
    6. Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain.
    7. Procollagen is shipped to the Golgi apparatus
      Golgi apparatus
      The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....

      , where it is packaged and secreted by exocytosis
      Exocytosis
      Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...

      .
  2. Outside the cell
    1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase
      Procollagen peptidase
      Procollagen peptidase is an endopeptidase involved in the processing of collagen. The proteases removes the terminal peptides of the procollagen...

      .
    2. Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction
      Aldol reaction
      The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...

      ) by lysyl oxidase
      Lysyl oxidase
      Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene. Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.-...

       which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
    3. Collagen may be attached to cell membranes via several types of protein, including fibronectin
      Fibronectin
      Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...

       and integrin
      Integrin
      Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....

      .

Synthetic pathogenesis


Vitamin C deficiency causes scurvy
Scurvy
Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the synthesis of collagen in humans. The chemical name for vitamin C, ascorbic acid, is derived from the Latin name of scurvy, scorbutus, which also provides the adjective scorbutic...

, a serious and painful disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

 in which defective collagen prevents the formation of strong connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

. Gums
Gingiva
The gingiva , or gums, consists of the mucosal tissue that lies over the mandible and maxilla inside the mouth.-General description:...

 deteriorate and bleed, with loss of teeth; skin discolors, and wound
Wound
A wound is a type of injury in which skin is torn, cut or punctured , or where blunt force trauma causes a contusion . In pathology, it specifically refers to a sharp injury which damages the dermis of the skin.-Open:...

s do not heal. Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C.

An autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...

 such as lupus erythematosus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...

 or rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

 may attack healthy collagen fibers.

Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production.

Characteristics


Collagen is one of the long, fibrous structural proteins
Fibrous protein
Scleroproteins, or fibrous proteins, constitute one of the three main classes of proteins, alongside globular proteins and conjugated proteins.Keratin, collagen, elastin, and fibroin are all scleroproteins...

 whose functions are quite different from those of globular protein
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...

s such as enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s. Tough bundles of collagen called collagen fibers are a major component of the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

 that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength
Tensile strength
Ultimate tensile strength , often shortened to tensile strength or ultimate strength, is the maximum stress that a material can withstand while being stretched or pulled before necking, which is when the specimen's cross-section starts to significantly contract...

, and is the main component of fascia
Fascia
A fascia is a layer of fibrous tissue that permeates the human body. A fascia is a connective tissue that surrounds muscles, groups of muscles, blood vessels, and nerves, binding those structures together in much the same manner as plastic wrap can be used to hold the contents of sandwiches...

, cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...

, ligament
Ligament
In anatomy, the term ligament is used to denote any of three types of structures. Most commonly, it refers to fibrous tissue that connects bones to other bones and is also known as articular ligament, articular larua, fibrous ligament, or true ligament.Ligament can also refer to:* Peritoneal...

s, tendon
Tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...

s, bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...

 and skin. Along with soft keratin
Keratin
Keratin refers to a family of fibrous structural proteins. Keratin is the key of structural material making up the outer layer of human skin. It is also the key structural component of hair and nails...

, it is responsible for skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...

 strength and elasticity, and its degradation leads to wrinkle
Wrinkle
A wrinkle is a fold, ridge or crease in the skin. Skin wrinkles typically appear as a result of aging processes such as glycation or, temporarily, as the result of prolonged immersion in water. Wrinkling in the skin is caused by habitual facial expressions, aging, sun damage, smoking, poor...

s that accompany aging. It strengthens blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s and plays a role in tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

 development. It is present in the cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...

 and lens of the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...

 in crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...

line form.

Uses


Collagen has a wide variety of applications, from food to medical. For instance, it is used in cosmetic surgery
Plastic surgery
Plastic surgery is a medical specialty concerned with the correction or restoration of form and function. Though cosmetic or aesthetic surgery is the best-known kind of plastic surgery, most plastic surgery is not cosmetic: plastic surgery includes many types of reconstructive surgery, hand...

 and burns surgery
Burn (injury)
A burn is a type of injury to flesh caused by heat, electricity, chemicals, light, radiation or friction. Most burns affect only the skin . Rarely, deeper tissues, such as muscle, bone, and blood vessels can also be injured...

. Hydrolyzed collagen can play an important role in weight management, as a protein, it can be advantageously used for its satiating power. It is widely used in the form of collagen casings
Casing (sausage)
Casing, sausage casing, or sausage skin is the material that encloses the filling of a sausage. Casings are divided into two categories, natural and artificial...

 for sausages.

If collagen is sufficiently denatured, e.g. by heating, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g. random coil
Random coil
A random coil is a polymer conformation where the monomer subunits are oriented randomly while still being bonded to adjacent units. It is not one specific shape, but a statistical distribution of shapes for all the chains in a population of macromolecules...

s. This process describes the formation of gelatin
Gelatin
Gelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...

, which is used in many food
Food
Food is any substance consumed to provide nutritional support for the body. It is usually of plant or animal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals...

s, including flavored gelatin dessert
Gelatin dessert
Gelatin desserts are desserts made with sweetened and flavored gelatin. They can be made by combining plain gelatin with other ingredients or by using a premixed blend of gelatin with additives...

s. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.
From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not contain all the essential amino acid
Essential amino acid
An essential amino acid or indispensable amino acid is an amino acid that cannot be synthesized de novo by the organism , and therefore must be supplied in the diet.-Essentiality vs. conditional essentiality in humans:...

s in the proportions that the human body requires—they are not 'complete protein
Complete protein
A complete protein is a source of protein that contains an adequate proportion of all nine of the essential amino acids necessary for the dietary needs of humans or other animals...

s' (as defined by food science, not that they are partially structured). Manufacturers of collagen-based dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...

s claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown strong evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition (such as normal aging, dry skin, arthritis etc.) rather than just a protein deficiency.

From the Greek for glue, kolla, the word collagen means "glue
Animal glue
An animal glue is an adhesive that is created by prolonged boiling of animal connective tissue.These protein colloid glues are formed through hydrolysis of the collagen from skins, bones, tendons, and other tissues, similar to gelatin. The word "collagen" itself derives from Greek κόλλα kolla, glue...

 producer" and refers to the early process of boiling the skin and sinews
Tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...

 of horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

s and other animals to obtain glue. Collagen adhesive was used by Egypt
Egypt
Egypt , officially the Arab Republic of Egypt, Arabic: , is a country mainly in North Africa, with the Sinai Peninsula forming a land bridge in Southwest Asia. Egypt is thus a transcontinental country, and a major power in Africa, the Mediterranean Basin, the Middle East and the Muslim world...

ians about 4,000 years ago, and Native Americans
Native Americans in the United States
Native Americans in the United States are the indigenous peoples in North America within the boundaries of the present-day continental United States, parts of Alaska, and the island state of Hawaii. They are composed of numerous, distinct tribes, states, and ethnic groups, many of which survive as...

 used it in bows
Bow (weapon)
The bow and arrow is a projectile weapon system that predates recorded history and is common to most cultures.-Description:A bow is a flexible arc that shoots aerodynamic projectiles by means of elastic energy. Essentially, the bow is a form of spring powered by a string or cord...

 about 1,500 years ago. The oldest glue in the world, carbon-dated
Radiocarbon dating
Radiocarbon dating is a radiometric dating method that uses the naturally occurring radioisotope carbon-14 to estimate the age of carbon-bearing materials up to about 58,000 to 62,000 years. Raw, i.e. uncalibrated, radiocarbon ages are usually reported in radiocarbon years "Before Present" ,...

 as more than 8,000 years old, was found to be collagen—used as a protective lining on rope baskets and embroidered
Embroidery
Embroidery is the art or handicraft of decorating fabric or other materials with needle and thread or yarn. Embroidery may also incorporate other materials such as metal strips, pearls, beads, quills, and sequins....

 fabric
Textile
A textile or cloth is a flexible woven material consisting of a network of natural or artificial fibres often referred to as thread or yarn. Yarn is produced by spinning raw fibres of wool, flax, cotton, or other material to produce long strands...

s, and to hold utensils together; also in crisscross decorations on human
Human
Humans are the only living species in the Homo genus...

 skull
Human skull
The human skull is a bony structure, skeleton, that is in the human head and which supports the structures of the face and forms a cavity for the brain.In humans, the adult skull is normally made up of 22 bones...

s. Collagen normally converts to gelatin, but survived due to the dry conditions. Animal glues are thermoplastic
Thermoplastic
Thermoplastic, also known as a thermosoftening plastic, is a polymer that turns to a liquid when heated and freezes to a very glassy state when cooled sufficiently...

, softening again upon reheating, and so they are still used in making musical instrument
Musical instrument
A musical instrument is a device created or adapted for the purpose of making musical sounds. In principle, any object that produces sound can serve as a musical instrument—it is through purpose that the object becomes a musical instrument. The history of musical instruments dates back to the...

s such as fine violin
Violin
The violin is a string instrument, usually with four strings tuned in perfect fifths. It is the smallest, highest-pitched member of the violin family of string instruments, which includes the viola and cello....

s and guitar
Guitar
The guitar is a plucked string instrument, usually played with fingers or a pick. The guitar consists of a body with a rigid neck to which the strings, generally six in number, are attached. Guitars are traditionally constructed of various woods and strung with animal gut or, more recently, with...

s, which may have to be reopened for repairs—an application incompatible with tough, synthetic
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 plastic
Plastic
A plastic material is any of a wide range of synthetic or semi-synthetic organic solids used in the manufacture of industrial products. Plastics are typically polymers of high molecular mass, and may contain other substances to improve performance and/or reduce production costs...

 adhesives, which are permanent. Animal sinews and skins, including leather
Leather
Leather is a durable and flexible material created via the tanning of putrescible animal rawhide and skin, primarily cattlehide. It can be produced through different manufacturing processes, ranging from cottage industry to heavy industry.-Forms:...

, have been used to make useful articles for millennia.

Gelatin-resorcinol
Resorcinol
Resorcinol is a dihydroxy benzene. It is the 1,3-isomer of benzenediol with the formula C6H42.-Nomenclature:Benzene-1,3-diol is the name recommended by the International Union of Pure and Applied Chemistry in its 1993 Recommendations for the Nomenclature of Organic Chemistry.-Production:It is...

-formaldehyde
Formaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...

 glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial
Glyoxal
Glyoxal is an organic compound with the formula OCHCHO. This yellow colored liquid is the smallest dialdehyde . Its tautomer acetylenediol is unstable.-Production:...

) has been used to repair experimental incisions in rabbit
Rabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...

 lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

s.

Cardiac applications



The four dense collagen valve
Valve
A valve is a device that regulates, directs or controls the flow of a fluid by opening, closing, or partially obstructing various passageways. Valves are technically pipe fittings, but are usually discussed as a separate category...

 rings, the central body of the heart and the cardiac skeleton
Cardiac skeleton
The cardiac skeleton, sometimes called the fibrous skeleton of the heart, is the structure of dense connective tissue in the heart that separates the atria from the ventricles...

 of the heart are histologically bound to the myocardium. Collagen contribution to heart performance summarily represents an essential, unique and moving solid anchor opposed to the fluid mechanics
Fluid mechanics
Fluid mechanics is the study of fluids and the forces on them. Fluid mechanics can be divided into fluid statics, the study of fluids at rest; fluid kinematics, the study of fluids in motion; and fluid dynamics, the study of the effect of forces on fluid motion...

 of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 within the heart. This structure is an impermeable firewall that excludes both blood and electrical influence (except through anatomical channels) from the upper to the lower chambers of the heart. As proof, one could posit that atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

 almost never deteriorates to ventricular fibrillation
Ventricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...

.
Individual valvular leaflets are held in sail
Sail
A sail is any type of surface intended to move a vessel, vehicle or rotor by being placed in a wind—in essence a propulsion wing. Sails are used in sailing.-History of sails:...

 shape by collagen under variable pressure
Pressure
Pressure is the force per unit area applied in a direction perpendicular to the surface of an object. Gauge pressure is the pressure relative to the local atmospheric or ambient pressure.- Definition :...

. Calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 deposition within collagen occurs as a natural consequence of aging. Calcium rich fixed points in an otherwise moving display of blood and muscle enable current cardiac imaging
Cardiac imaging
Cardiac imaging techniques include Coronary catheterization, echocardiogram, and Intravascular ultrasound.-Coronary catheterization:Coronary catheterization uses pressure monitoring and blood sampling through a catheter inserted into the heart through blood vessels in the leg to determine the...

 technology to arrive at ratios essentially stating blood in cardiac input
Cardiac input
Cardiac input is the inverse operation of cardiac output .Cardiac output implies ejection fraction.Ejection fraction is an easily understood and inexpensively imaged mathematical model of systole....

 and blood out cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...

. Specified imaging such as calcium scoring illustrates the utility of this methodology, especially in an aging patient subject to pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....

 of the collagen underpinning.

Cosmetic surgery


Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes. Both human and bovine collagen is widely used as dermal fillers for treatment of wrinkles and skin aging. Some points of interest are:
  1. when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and
  2. most medical collagen is derived from young beef cattle (bovine) from certified BSE (bovine spongiform encephalopathy
    Bovine spongiform encephalopathy
    Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...

    ) free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia, Brazil and New Zealand.
  3. porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes.
  4. alternatives using the patient's own fat
    Fat
    Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

    , hyaluronic acid or polyacrylamide
    Polyacrylamide
    Polyacrylamide is a polymer formed from acrylamide subunits. It can be synthesized as a simple linear-chain structure or cross-linked, typically using N,N-methylenebisacrylamide. Polyacrylamide is not toxic...

     gels which are readily available.

Reconstructive surgical uses


Collagens are widely employed in the construction of artificial skin
Artificial skin
Artificial skin can refer to skin grown in a laboratory that can be used as skin replacement for people who have suffered skin trauma such as severe burns or skin diseases.Alternatively, it can also refer to skin synthetically produced for other purposes....

 substitutes used in the management of severe burns
Burn (injury)
A burn is a type of injury to flesh caused by heat, electricity, chemicals, light, radiation or friction. Most burns affect only the skin . Rarely, deeper tissues, such as muscle, bone, and blood vessels can also be injured...

. These collagens may be derived from bovine, equine or porcine, and even human sources and are sometimes used in combination with silicone
Silicone
Silicones are inert, synthetic compounds with a variety of forms and uses. Typically heat-resistant and rubber-like, they are used in sealants, adhesives, lubricants, medical applications , cookware, and insulation....

s, glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...

s, fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s, growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

s and other substances.

Collagen is also sold as a pill commercially as a joint mobility supplement with poor references. Because proteins are broken down into amino acids before absorption, there is no reason for orally ingested collagen to affect connective tissue in the body, except through the effect of individual amino acid supplementation.

Although it cannot be absorbed through the skin, collagen is now being used as a main ingredient for some cosmetic makeup.

Collagen is also frequently used in scientific research applications for cell culture, studying cell behavior and cellular interactions with the extracellular environment. Suppliers such as Trevigen manufacture rat and bovine Collagen I and mouse Collagen IV.

Wound care management uses


Collagen is one of the body’s key natural resources and a component of skin tissue that can benefit all stages of the wound healing process. When collagen is made available to the wound bed, closure can occur. Wound deterioration, followed sometimes by procedures such as amputation, can thus be avoided.

Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing:
• Guiding Function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix.
• Chemotactic Properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in healing.
• Nucleation: Collagen, in the presence of certain neutral salt molecules can act as a nucleating agent causing formation of fibrillar structures. A collagen wound dressing might serve as a guide for orienting new collagen deposition and capillary growth.
• Hemostatic properties: Blood platelets interact with the collagen to make a hemostatic plug.

Paleontology and Archaeology


Because the synthesis of collagen requires a high level of atmospheric oxygen, complex animals may not have been able to evolve until the atmosphere was oxygenic enough for collagen synthesis. The origin of collagen may have allowed cuticle, shell and muscle formation. However, the preservation of collagen in the fossil record is very scarce. There is mounting evidence—which remains controversial—that collagen has been preserved in dinosaur specimens dated as long ago as .

Also worth noting are the actinofibrils, collagen fibers present on the wings of pterosaurs.

Collagen is regularly extracted from the bones of prehistoric animals for use in radiocarbon dating and stable isotope
Stable isotope
Stable isotopes are chemical isotopes that may or may not be radioactive, but if radioactive, have half-lives too long to be measured.Only 90 nuclides from the first 40 elements are energetically stable to any kind of decay save proton decay, in theory...

 analysis. The integrity of the molecule can be assessed with a number of measurements (collagen yield, C:N ratio, %C and %N) . With respect to radiometric dating, extracted collagen produces a 'more pure' form of carbon that can be dated than does bulk bone, which contains a high amount of carbonated apatite, which is prone to exchange with environmental sources of carbon, causing contamination
Contamination
Contamination is the presence of a minor and unwanted constituent in material, physical body, natural environment, at a workplace, etc.-Specifics:"Contamination" also has more specific meanings in science:...

. Stable isotope analysis of carbon and nitrogen are commonly used to study diet in past populations of humans, as well as to reconstruct ecological conditions.

Art


Using the atomic coordinates deposited in the Protein Data Bank
Protein Data Bank
The Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....

, German-American artist Julian Voss-Andreae
Julian Voss-Andreae
Julian Voss-Andreae is a German sculptor living and working in the U.S.Voss-Andreae started out as a painter and later studied experimental physics at the universities of Berlin, Edinburgh and Vienna...

 has created sculptures based on the structure of collagen and other proteins. In Unraveling Collagen the triangular cut-outs reveal the dominant force lines, reminiscent of contemporary steel construction.

See also

  • Hydrolyzed collagen, a common form in which collagen is sold as a supplement.
  • Animal glue
    Animal glue
    An animal glue is an adhesive that is created by prolonged boiling of animal connective tissue.These protein colloid glues are formed through hydrolysis of the collagen from skins, bones, tendons, and other tissues, similar to gelatin. The word "collagen" itself derives from Greek κόλλα kolla, glue...

  • Gelatine
  • Fibrous protein
    Fibrous protein
    Scleroproteins, or fibrous proteins, constitute one of the three main classes of proteins, alongside globular proteins and conjugated proteins.Keratin, collagen, elastin, and fibroin are all scleroproteins...

  • Osteoid
    Osteoid
    In histology, osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue. Osteoblasts begin the process of forming bone tissue by secreting the osteoid as several specific proteins...

    , collagen containing component of bone

  • Lysyl oxidase
    Lysyl oxidase
    Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene. Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.-...

     and LOXL1
    LOXL1
    Lysyl oxidase-like 1, also known as LOXL1, is an enzyme which in humans is encoded by the LOXL1 gene.- Function :This gene encodes a member of the lysyl oxidase gene family...

    , LOXL2
    LOXL2
    Lysyl oxidase homolog 2 is an enzyme that in humans is encoded by the LOXL2 gene.According to a BBC article on 2/22/11, "scientists at the UK's Institute of Cancer Research have prevented breast cancer spreading to other organs in mice by blocking the enzyme LOXL2 ". Their findings were published...

    , LOXL3
    LOXL3
    Lysyl oxidase homolog 3 is an enzyme that in humans is encoded by the LOXL3 gene.-Further reading:...

    , LOXL4
    LOXL4
    Lysyl oxidase homolog 4 is an enzyme that in humans is encoded by the LOXL4 gene.-Further reading:...

     in collagen formation
  • Collagenase, the enzyme involved in collagen breakdown and remodelling. For more on other protease
    Protease
    A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

    s that target collagen see The Proteolysis Map
    The Proteolysis Map
    The Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...


  • Ehlers-Danlos Syndrome
    Ehlers-Danlos syndrome
    Ehlers–Danlos syndrome is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen . The collagen in connective tissue helps tissues to resist deformation...

  • Hypermobility Syndrome
  • Marfan Syndrome
    Marfan syndrome
    Marfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers....

    , a genetic disease with defective fibrillin 1

External links