Titin
Encyclopedia
Titin also known as connectin, is a protein
that in humans is encoded by the TTN gene
. Titin is a giant protein that functions as a molecular spring which is responsible for the passive elasticity of muscle. It is composed of 244 individually folded protein domain
s connected by unstructured peptide
sequences. These domains unfold
when the protein is stretched and refold
when the tension is removed.
Titin is the largest known polypeptide. Furthermore the gene for titin contains the largest number of exon
s (363) discovered in any single gene.
Titin is important in the contraction of striated muscle
tissues. It connects the Z line to the M line in the sarcomere
. The protein contributes to force transmission at the Z line and resting tension in the I band region. It limits the range of motion of the sarcomere in tension, thus contributing to the passive stiffness of muscle. Variations in the sequence of titin between different types of muscle (e.g., cardiac or skeletal) has been correlated with differences in the mechanical properties of these muscles.
s are produced in different striated muscle tissues as a result of alternative splicing
. All but one of these isoforms are in the range of ~27,000 to ~33,000 amino acid residues in length. The exception is the small cardiac novex-3 isoform which is only 5,604 amino acid residues in length. The following table lists the known titin isoforms:
s, with the molecular weight of the mature "canonical" isoform of the protein being approximately 3,816,188.13 Da
. Its mouse homologue is even larger, comprising 35,213 amino acids with a MW of 3,906,487.6 Da
. It has a theoretical isoelectric point
of 6.01. The protein's empirical chemical formula
is C169 723H270 464N45 688O52 243S912. It has a theoretical instability index
(II) of 42.41, classifying the protein as unstable. The protein's in vivo
half-life
, the time it takes for half of the amount of protein in a cell to break down after its synthesis in the cell, is predicted to be approximately 30 hours (in mammalian reticulocyte
s).
Titin consists primarily of a linear array of two types of modules (also referred to as protein domain
s; 244 copies in total): type I (fibronectin type III domain
; 132 copies) and type II (immunoglobulin domain
; 112 copies). This linear array is further organized into two regions:
N-terminal I-band: acts as the elastic part of the molecule and is composed mainly of type II modules. More specifically the I-band contains two regions of tandem type II immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. Titin is found between the myosin
thick filament and the Z disk.
C-terminal A-band: is thought to act as a protein-ruler and possesses kinase
activity. The A-band is composed of alternating type I and II modules with super-repeat segments. These have been shown to align to the 43 nm axial repeats of myosin thick filaments with immunoglobulin domains correlating to myosin crowns.
Titin is a large abundant protein of striated muscle. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere
respectively so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle-associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosome
s. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Of the many titin variants identified, five for which complete transcript information is available are described.
Titin interacts with many sarcomeric
proteins including:
hypertrophic cardiomyopathy
9 and tibial muscular dystrophy
. Autoantibodies to titin are produced in patients with the autoimmune disease scleroderma
.
(a giant deity, anything of great size).
As the largest known protein, titin also has the longest IUPAC name. The full chemical name, which starts methionyl
... and ends ...isoleucine
, contains 189,819 letters and is sometimes stated to be the longest word in the English language
, or any language
. However, lexicographers regard generic names of chemical compound
s as verbal formulae
rather than English words.
with:
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...
that in humans is encoded by the TTN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Titin is a giant protein that functions as a molecular spring which is responsible for the passive elasticity of muscle. It is composed of 244 individually folded protein domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
s connected by unstructured 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...
sequences. These domains unfold
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
when the protein is stretched and refold
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
when the tension is removed.
Titin is the largest known polypeptide. Furthermore the gene for titin contains the largest number of exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s (363) discovered in any single gene.
Titin is important in the contraction of striated muscle
Striated muscle
Striated muscle tissue is a form of fibers that are combined into parallel fibers. More specifically, it can refer to:* Cardiac muscle .* Skeletal muscle* Branchiomeric muscles...
tissues. It connects the Z line to the M line in the sarcomere
Sarcomere
A sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
. The protein contributes to force transmission at the Z line and resting tension in the I band region. It limits the range of motion of the sarcomere in tension, thus contributing to the passive stiffness of muscle. Variations in the sequence of titin between different types of muscle (e.g., cardiac or skeletal) has been correlated with differences in the mechanical properties of these muscles.
Isoforms
A number of titin isoformProtein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
s are produced in different striated muscle tissues as a result of alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
. All but one of these isoforms are in the range of ~27,000 to ~33,000 amino acid residues in length. The exception is the small cardiac novex-3 isoform which is only 5,604 amino acid residues in length. The following table lists the known titin isoforms:
| Isoform | alias/description | length |
|---|---|---|
| Q8WZ42-1 | the "canonical" full length sequence | 34,350 |
| Q8WZ42-3 | small cardiac N2-B | 26,926 |
| Q8WZ42-4 | soleus | 33,445 |
| Q8WZ42-6 | small cardiac novex-3, phosphorylated on Thr-5304 and Ser-5306. |
5,604 |
| Q8WZ42-7 | cardiac novex-2 | 27,118 |
| Q8WZ42-8 | cardiac novex-1 | 27,051 |
Structure
Titin is the largest known protein; its human variant consists of 34,350 amino acidAmino 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, with the molecular weight of the mature "canonical" isoform of the protein being approximately 3,816,188.13 Da
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
. Its mouse homologue is even larger, comprising 35,213 amino acids with a MW of 3,906,487.6 Da
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
. It has a theoretical isoelectric point
Isoelectric point
The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge....
of 6.01. The protein's empirical chemical formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
is C169 723H270 464N45 688O52 243S912. It has a theoretical instability index
Instability index
The Instability index is a measure of proteins, used to determine whether it will be stable in a test tube.If the index is less than 40, then it is probably stable in the test tube. If it is greater then it is probably not stable....
(II) of 42.41, classifying the protein as unstable. The protein's in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
, the time it takes for half of the amount of protein in a cell to break down after its synthesis in the cell, is predicted to be approximately 30 hours (in mammalian reticulocyte
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
s).
Titin consists primarily of a linear array of two types of modules (also referred to as protein domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
s; 244 copies in total): type I (fibronectin type III domain
Fibronectin type III domain
The Fibronectin type III domain is an evolutionary conserved protein domain that is widely found in animal proteins. The fibronectin protein in which this domain was first identified contains 16 copies of this domain. The domain is about 100 amino acids long and possesses a beta sandwich...
; 132 copies) and type II (immunoglobulin domain
Immunoglobulin domain
The immunoglobulin domain is a type of protein domain that consists of a 2-layer sandwich of between 7 and 9 antiparallel β-strands arranged in two β-sheets with a Greek key topology....
; 112 copies). This linear array is further organized into two regions:
N-terminal I-band: acts as the elastic part of the molecule and is composed mainly of type II modules. More specifically the I-band contains two regions of tandem type II immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. Titin is found between the myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
thick filament and the Z disk.
C-terminal A-band: is thought to act as a protein-ruler and possesses kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activity. The A-band is composed of alternating type I and II modules with super-repeat segments. These have been shown to align to the 43 nm axial repeats of myosin thick filaments with immunoglobulin domains correlating to myosin crowns.
Function
Sarcomere
A sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
respectively so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle-associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Of the many titin variants identified, five for which complete transcript information is available are described.
Titin interacts with many sarcomeric
Sarcomere
A sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
proteins including:
- Z line region: telethoninTCAP (gene)Telethonin is a protein that in humans is encoded by the TCAP gene.-Interactions:Telethonin has been shown to interact with Titin, MYOZ1 and ANKRD2.- External links :*...
and alpha-actininACTN1Alpha-actinin-1 is a protein that in humans is encoded by the ACTN1 gene.-Interactions:Actinin, alpha 1 has been shown to interact with PDLIM1, Collagen, type XVII, alpha 1, CDK5R1, Zyxin, Protein kinase N1, GIPC1, SSX2IP and CDK5R2.... - I band region: calpain-3CAPN3Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.-External links:* The MEROPS online database for peptidases and their inhibitors: ** LOVD mutation database:...
and obscurinOBSCNObscurin is a protein that in humans is encoded by the OBSCN gene.-Interactions:OBSCN has been shown to interact with Titin and ANK1.-Further reading:... - M line region: myosin-binding protein C, calmodulin 1Calmodulin 1Calmodulin 1 is a protein that in humans is encoded by the CALM1 gene.- Function :Calmodulin 1 is the archetype of the family of calcium-modulated proteins of which nearly 20 members have been found. They are identified by their occurrence in the cytosol or on membranes facing the cytosol and by a...
, CAPN3CAPN3Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.-External links:* The MEROPS online database for peptidases and their inhibitors: ** LOVD mutation database:...
, and MURF1TRIM63E3 ubiquitin-protein ligase TRIM63 is an enzyme that in humans is encoded by the TRIM63 gene.-Interactions:TRIM63 has been shown to interact with Titin, GMEB1 and SUMO2.-Further reading:...
Clinical relevance
Mutations in this gene are associated with familialFamily
In human context, a family is a group of people affiliated by consanguinity, affinity, or co-residence. In most societies it is the principal institution for the socialization of children...
hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is a disease of the myocardium in which a portion of the myocardium is hypertrophied without any obvious cause...
9 and tibial muscular dystrophy
Distal muscular dystrophy
Distal muscular dystrophy is a group of disorders characterized by onset in the hands or feet.Many types involve dysferlin, but it has been suggested that not all cases do.Types include:...
. Autoantibodies to titin are produced in patients with the autoimmune disease 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:...
.
Linguistic significance
The name titin is derived from the Greek TitanTitan (mythology)
In Greek mythology, the Titans were a race of powerful deities, descendants of Gaia and Uranus, that ruled during the legendary Golden Age....
(a giant deity, anything of great size).
As the largest known protein, titin also has the longest IUPAC name. The full chemical name, which starts methionyl
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...
... and ends ...isoleucine
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....
, contains 189,819 letters and is sometimes stated to be the longest word in the English language
Longest word in English
The identity of the longest word in English depends upon the definition of what constitutes a word in the English language, as well as how length should be compared...
, or any language
Longest words
The longest word in any given language depends on the word formation rules of each specific language, and on the types of words allowed for consideration. Agglutinative languages allow for the creation of long words via compounding. Even non-agglutinative languages may allow word formation of...
. However, lexicographers regard generic names of chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
s as verbal formulae
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
rather than English words.
Interactions
Titin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- ANK1ANK1Ankyrin 1, erythrocytic, also known as ANK1, is a protein which in humans is encoded by the ANK1 gene.-Tissue distribution:The protein encoded by this gene, Ankyrin 1, is the prototype of the ankyrin family, was first discovered in erythrocytes, but since has also been found in brain and...
, - ANKRD1ANKRD1Ankyrin repeat domain-containing protein 1 is a protein that in humans is encoded by the ANKRD1 gene.-Interactions:ANKRD1 has been shown to interact with Titin and MYPN.-Further reading:...
, - ANKRD23ANKRD23Ankyrin repeat domain-containing protein 23 is a protein that in humans is encoded by the ANKRD23 gene.-Interactions:ANKRD23 has been shown to interact with Titin and MYPN.-Further reading:...
- CAPN3CAPN3Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.-External links:* The MEROPS online database for peptidases and their inhibitors: ** LOVD mutation database:...
, - FHL2FHL2Four and a half LIM domains protein 2 is a protein that in humans is encoded by the FHL2 gene.-Interactions:FHL2 has been shown to interact with Beta-catenin, Titin, Zinc finger and BTB domain-containing protein 16, Integrin, beta 6, Androgen receptor, ITGA7, CREB1, MAPK1, CD49c, ZNF638, BRCA1,...
, - OBSCNOBSCNObscurin is a protein that in humans is encoded by the OBSCN gene.-Interactions:OBSCN has been shown to interact with Titin and ANK1.-Further reading:...
, - TCAP, and
- TRIM63TRIM63E3 ubiquitin-protein ligase TRIM63 is an enzyme that in humans is encoded by the TRIM63 gene.-Interactions:TRIM63 has been shown to interact with Titin, GMEB1 and SUMO2.-Further reading:...
.