Ubiquitin is a small,
highly-conservedIn biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
regulatory
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
that is
ubiquitously expressed in eukaryotes.
Ubiquitination (or
ubiquitylation) refers to the post-translational modification of a protein by the covalent attachment (via an
isopeptide bondAn isopeptide bond is an amide bond that is not present on the main chain of a protein. The bond forms between a side-chain carboxyl group and amino group....
) of one or more ubiquitin monomers.
The most prominent function of ubiquitin is labeling proteins for
proteasomalProteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
degradation. Besides this function, ubiquitination also controls the stability, function, and intracellular localization of a wide variety of proteins.
Ubiquitin is a small,
highly-conservedIn biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
regulatory
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
that is
ubiquitously expressed in eukaryotes.
Ubiquitination (or
ubiquitylation) refers to the post-translational modification of a protein by the covalent attachment (via an
isopeptide bondAn isopeptide bond is an amide bond that is not present on the main chain of a protein. The bond forms between a side-chain carboxyl group and amino group....
) of one or more ubiquitin monomers.
The most prominent function of ubiquitin is labeling proteins for
proteasomalProteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
degradation. Besides this function, ubiquitination also controls the stability, function, and intracellular localization of a wide variety of proteins. The ubiquitylation (or ubiquitination) cascade is started by the E1 enzyme.
Identification
Ubiquitin (originally,
ubiquitous immunopoietic polypeptide) was first identified in 1975 as an 8.5-
kDaThe unified atomic mass unit or atomic mass unit , or dalton or, sometimes, universal mass unit , is a unit of mass used to express atomic and molecular masses...
protein of unknown function expressed universally in living cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s in groundbreaking work performed at
Fox Chase Cancer CenterThe Fox Chase Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center research facility and hospital located in the Fox Chase section of Philadelphia, Pennsylvania, United States. The main facilities of the center are located on property adjoining Burholme Park...
by
Aaron CiechanoverAaron Ciechanover is an Israeli biologist, and Nobel laureate in Chemistry.- Biography :Born in Haifa, British Mandate of Palestine, Ciechanover received his Master of Science degree in 1971 and his M.D. in 1974 from the Hadassah Medical School of the Hebrew University in Jerusalem...
,
Avram HershkoAvram Hershko is an Israeli biochemist and Nobel laureate in Chemistry.-Biography:Born Herskó Ferenc in Karcag, Hungary, Hershko emigrated to Israel in 1950. Received his M.D. in 1965 and his Ph. D in 1969 from the Hebrew University-Hadassah Medical School, Jerusalem, Israel...
, and
Irwin RoseIrwin A. Rose is an American biologist. Along with Aaron Ciechanover and Avram Hershko, he was awarded the 2004 Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation.-Biography:...
for which the
Nobel Prize in ChemistryThe Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...
was awarded in 2004.
The ubiquitylation system was initially characterised as an
ATPAdenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
-dependent proteolytic system present in cellular extracts. A heat-stable
polypeptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate
lysozymeLysozyme, also known as muramidase or N-acetylmuramide glycanhydrolase, are a family of enzymes which damage bacterial cell walls by catalyzing hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in a peptidoglycan and between N-acetyl-D-glucosamine...
in an
ATPAdenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
- and
MgMagnesium is a chemical element with the symbol Mg, atomic number 12 and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the earth's crust by mass, although ninth in the Universe as a whole...
2+-dependent process. Multiple APF-1 molecules were linked to a single
substrateIn biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
molecule by an isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate
lysineLysine is an α-amino acid with the chemical formula HO
2CCH
4NH
2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.Lysine is a base, as are arginine and histidine...
residues.
The protein
Ubiquitin properties (human)
| Number of residues |
76 |
Molecular massThe molecular mass of a substance, frequently referred to by the older term molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u...
|
8564.47 Da |
| Isoelectric point The isoelectric point , sometimes abbreviated to IEP, is the pH at which a particular molecule or surface carries no net electrical charge....
(pI) |
6.79 |
| Gene names |
RPS27A 40S ribosomal protein S27a is a protein that in humans is encoded by the RPS27A gene.-Further reading:...
(UBA80, UBCEP1), UBA5260S ribosomal protein L40 is a protein that in humans is encoded by the UBA52 gene.-Further reading:...
(UBCEP2), UBBUbiquitin is a protein that in humans is encoded by the UBB gene.-Further reading:...
, UBCUbiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
|
Ubiquitin is a small
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
that exists in all
eukaryoticA eukaryote is an organism whose cells contain complex structures enclosed within membranes. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear envelope, within which the genetic material is carried...
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos...
s. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
s and has a
molecular massThe molecular mass of a substance, frequently referred to by the older term molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u...
of about 8.5 kDa. Key features include its C-terminal tail and the 7
LysLysine is an α-amino acid with the chemical formula HO
2CCH
4NH
2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.Lysine is a base, as are arginine and histidine...
residues. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96% sequence identity. The human ubiquitin sequence in one-letter code (lysine residues in bold):
| MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG |
Ubiquitination (Ubiquitylation)
The process of marking a protein with ubiquitin (ubiquitylation or ubiquitination) consists of a series of steps:
- Activation of ubiquitin: Ubiquitin is activated in a two-step reaction by an E1 ubiquitin-activating enzyme in a process requiring ATP
Adenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
as an energy source. The initial step involves production of a ubiquitin-adenylate intermediate. The second step transfers ubiquitin to the E1 active siteThe active site of an enzyme contains the catalytic and binding sites. The structure and chemical properties of the active site allow the recognition and binding of the substrate....
cysteineCysteine is an α-amino acid with the chemical formula HO
2CCHCH
2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is nonpolar and thus cysteine is usually classified as...
residue, with release of AMPAdenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is found in RNA. It is an ester of phosphoric acid and the nucleoside adenosine...
. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl groupIn organic chemistry, a thiol is a compound that contains the functional group composed of a sulfur-hydrogen bond . Being the sulfur analogue of an alcohol group , this functional group is referred to either as a thiol group or a sulfhydryl group...
.
- Transfer of ubiquitin from E1 to the active site
The active site of an enzyme contains the catalytic and binding sites. The structure and chemical properties of the active site allow the recognition and binding of the substrate....
cysteine of a ubiquitin-conjugating enzymeUbiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome.The ubiquitination process covalently attaches ubiquitin, a short protein of 76...
E2 via a trans(thio)esterification reaction. Mammalian genomes contain 30-40 UBCs.
- The final step of the ubiquitylation cascade creates an isopeptide bond between a lysine of the target protein and the C-terminal glycine of ubiquitin. In general, this step requires the activity of one of the hundreds of E3 ubiquitin-protein ligases (often termed simply ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 Ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
). E3 enzymes function as the substrateIn biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
recognition modules of the system and are capable of interaction with both E2 and substrateIn biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
.
In the ubiquitination cascade E1 can bind with dozens of E2s which can bind with hundreds of E3s in a hierarchical way. Other ubiquitin-like proteins (ULPs) are also modified via the E1–E2–E3 cascade.
E3
E3 enzymes possess one of two
domainsA 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...
:
-
- The HECT (Homologous to the E6-AP Carboxyl Terminus) domain
- The RING
The RING finger domain is a type of zinc finger which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids...
(Really Interesting New Gene) domain (or the closely-related U-box domain)
- Transfer can occur in two ways:
-
- Directly from E2, catalysed by RING domain E3s.
- Via an E3 enzyme, catalysed by HECT domain E3s. In this case, a covalent E3-ubiquitin intermediate is formed before transfer of ubiquitin to the substrate protein.
Multisubunit E3 ubiquitin ligases
The
anaphase-promoting complexAnaphase-promoting complex , also called cyclosome, is a complex of several proteins which is activated during mitosis to initiate anaphase. The APC is an E3 ubiquitin ligase that marks target proteins for degradation by the 26S proteasome....
(APC) and the
SCF complexSkp, Cullin, F-box containing complex is a multi-protein E3 ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. It has important roles in the ubiquitylation of proteins involved in the cell cycle as well as having a role in the marking various other...
(for Skp1-Cullin-F-box protein complex) are two examples of multi-
subunitIn 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...
E3s involved in recognition and ubiquitination of specific target proteins for degradation by the
proteasomeProteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
.
Function and variety of ubiquitin modifications
Following addition of a single ubiquitin moiety to a protein substrate (monoubiquitination), further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain. In addition, some substrates are modified by addition of ubiquitin molecules to multiple lysine residues in a process termed multiubiquitination. As discussed, ubiquitin possesses a total of 7 lysine residues. Historically the original type of ubiquitin chains identified were those linked via lysine 48. However, more recent work has uncovered a wide variety of linkages involving all possible lysine residues and in addition chains assembled on the N-terminus of a ubiquitin molecule ("linear chains"). Work published in 2007 has demonstrated the formation of branched ubiquitin chains containing multiple linkage types. "Atypical" (non-lysine 48-linked) ubiquitin chains have been discussed in a review by Ikeda & Dikic.
The ubiquitination system functions in a wide variety of cellular processes, including:
- Antigen processing
- Apoptosis
- Biogenesis of organelles
- Cell cycle and division
- DNA transcription and repair
- Differentiation and development
- Immune response and inflammation
- Neural and muscular degeneration
- Morphogenesis of neural networks
- Modulation of cell surface receptors, ion channels and the secretory pathway
- Response to stress and extracellular modulators
- Ribosome biogenesis
- Viral infection
Lysine 48-linked chains
The most studied polyubiquitin chains - lysine48-linked - target proteins for destruction, a process known as
proteolysisProteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
. At least four ubiquitin molecules must be attached to lysine residues on the condemned protein in order for it to be recognised by the 26S-
proteasomeProteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. The
proteasomeProteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
is a complex, barrel-shaped structure with two chambers, within which proteolysis occurs. Proteins are rapidly degraded into small
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
s (usually 3-24
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use. Although the majority of proteasomal substrates are ubiquitinated, there are examples of non-ubiquitinated proteins being targeted to the proteasome.
Lysine 63-linked chains
Monoubiquitination
Ubiquitin can also mark
transmembrane proteinA transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them can be also extracted using denaturing agents.-Types:There are two basic...
s (for example,
receptorsIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
) for removal from
membranesA biological membrane or biomembrane is an enclosing or separating amphipathic layer that acts as a barrier within or around a cell. It is almost invariably a lipid bilayer, composed of a double layer of lipid molecules and proteins that may constitute close to 50% of membrane...
and fulfill several signaling roles within the cell. Cell-surface transmembrane molecules that are tagged with ubiquitin are often monoubiquitinated, and this modification alters the subcellular localization of the protein, often targeting the protein for destruction in lysosomes.
Histones are usually monoubiquitinated and associated with signaling or structural marking.
Genetic disorders
Some genetic disorders associated with ubiquitin are:
- The gene whose disruption causes Angelman syndrome
Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements especially hand-flapping, frequent laughter or smiling, and usually a happy demeanor. AS is a classic example of genetic imprinting in that it is...
, UBE3A, encodes a ubiquitin ligase (E3) enzyme termed E6-AP.
- The gene disrupted in Von Hippel-Lindau syndrome encodes a ubiquitin E3 ligase termed the VHL tumor suppressor or VHL gene.
- The gene disrupted in Liddle's Syndrome
Liddle syndrome is an autosomal dominant disorder characterized by early, and frequently severe, hypertension associated with low plasma renin activity, metabolic alkalosis due to hypokalemia, and hypoaldosteronism . It is one of several conditions with this unusual set of characteristics known...
results in disregulation of an epithelial Na+ channel (ENaC) and causes hypertension.
- Eight of the thirteen identified genes whose disruption causes Fanconi anemia
Fanconi anemia is a genetic disease that affects children and adults from all ethnic backgrounds. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi...
encode proteins that form a large ubiquitin ligase (E3) complex.
- mutations of the Cullin7 E3 ubiquitin ligase are linked to 3-M syndrome
3-M syndrome , is a rare hereditary growth retardation syndrome. The name 3-M originates from the initials of the three authors Miller, McKusick and Malvaux who first reported the syndrome in literature...
, an autosomal-recessive growth retardation disorder
Immunohistochemistry
AntibodiesAntibodies are gamma globulin proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses...
to ubiquitin are used in
histologyHistology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining a thin slice of tissue under a light microscope or electron microscope...
to identify abnormal accumulations of protein inside cells that are markers of disease. These accumulations are called inclusion bodies. Examples of such abnormal inclusions in cells are
- Neurofibrillary tangle
Neurofibrillary tangles are pathological protein aggregates found within neurons in cases of Alzheimer's disease. They were first described by Alois Alzheimer in one of his patients suffering from the disorder...
s in Alzheimer's diseaseAlzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was...
- Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells. They are identified under the microscope when histology is performed on the brain....
in Parkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions....
- Pick bodies
Pick bodies are silver-staining, spherical aggregations of tau protein in neurons associated with Pick's disease, a subtype of frontotemporal lobar degeneration. Pick bodies were first described by Czechoslovakian neurologist Arnold Pick in 1892....
in Pick's diseasePick's disease, also known as Pick disease and PiD, is a rare neurodegenerative disease. While the term Pick's disease was once used to represent a specific group of clinical syndromes with symptoms attributable to frontal and temporal lobe dysfunction, it is now used to mean a specific pathology...
- Inclusions in motor neuron disease and Huntington's Disease
Huntington's disease, chorea, or disorder , is an incurable neurodegenerative genetic disorder that affects muscle coordination and some cognitive functions, typically becoming noticeable in middle age. It is the most common genetic cause of abnormal involuntary writhing movements called chorea...
- Mallory bodies
In histopathology, a Mallory body, also known as alcoholic hyaline and Mallory's hyaline, is an inclusion found in the cytoplasm of liver cells....
in alcoholic liver diseaseAlcoholic liver disease is the major cause of liver disease in Western countries, . It arises from the excessive ingestion of alcohol.-Pathophysiology:-Fatty change:...
- Rosenthal fiber
A Rosenthal fiber is a thick, elongated, worm-like or "corkscrew" eosinophilic bundle that is found on H&E staining of the brain in the presence of long standing gliosis, occasional tumors, and some metabolic disorders.-Associated conditions:...
s in astrocyteAstrocytes are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a...
s
Ubiquitin-like modifiers
Although ubiquitin is the most well understood post-translation modifier, there is a growing family of ubiquitin-like proteins (UBLs) that modify cellular targets in a pathway that is parallel to, but distinct from, that of ubiquitin. Known UBLs include: small ubiquitin-like modifier (SUMO), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15 [ISG15]), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8, also called Rub1 in S. cerevisiae), human leukocyte antigen F associated (FAT10), autophagy-8 (ATG8) and -12 (ATG12), Fau ubiquitin-like protein (FUB1), MUB (membrane-anchored UBL), ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in
Schizosaccharomyces pombe). Whilst these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but contain the same structural fold. This fold is called a "ubiquitin fold" or sometimes called an ubiquit
on fold. FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise an ubiquitin-like domain e.g. the
S. cerevisiae spindle pole body duplication protein, Dsk2, and NER protein, Rad23, both contain N-terminal ubiquitin domains.
These related molecules have novel functions and influence diverse biological processes. There is also cross-regulation between the various conjugation pathways since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome, but rather function in diverse regulatory activities. Attachment of UBLs might alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization and influence protein stability.
UBLs are structurally similar to ubiquitin and are processed, activated, conjugated and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. These conjugates can be reversed by UBL-specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes.
Note: Ubiquitin is also used to mark paternal mitochondria for destruction during human fertilization.
See also
- Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly-regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
- Autophagin
Autophagin-1 is a unique cysteine protease responsible for the cleavage of the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation during autophagy...
- ERAD
Endoplasmic Reticulum Associated Protein Degradation designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome....
- SUMO protein
Small Ubiquitin-like Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function...
- SUMO enzymes
SUMO enzymatic cascade catalyzes the dynamic posttranslational modification process of sumoylation...
- SUMO network
SUMO network consists of enzymes and substrates involved in the dynamic posttranslational modification process of sumoylation .-Network members:...
- Autophagy network
Autophagy network consists of enzymes and substrates involved in the degradation of a cell's own components.-Network members:The Autophagy network members as published in the last 500 newest PubMed entries are depicted organically by Cytoscape in the figure on the right and are listed below as...
- Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 Ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
Further reading
- Essays in Biochemistry, Volume 41 (2005): The Ubiquitin-Proteasome System (Portland Press)
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