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508  structures 901  species 16  interactions 11560  sequences 265  architectures

Family: ubiquitin (PF00240)

Summary: Ubiquitin family

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Ubiquitin Edit Wikipedia article

Ubiquitin family
Ubiquitin cartoon-2-.png
A diagram of ubiquitin. The seven lysine sidechains are shown in orange.
Identifiers
Symbol ubiquitin
Pfam PF00240
InterPro IPR000626
PROSITE PDOC00271
SCOP 1aar
SUPERFAMILY 1aar

Ubiquitin is a small (8.5 kDa) regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms. It was discovered in 1975[1] by Goldstein and further characterized throughout the 1970s and 80s.[2] There are four genes in the human genome that produce ubiquitin; UBB, UBC, UBA52 and RPS27A.[3]

Ubiquitination is a post translational modification (an addition to a protein after it has been made) where ubiquitin is attached to a substrate protein. The addition of ubiquitin can affect proteins in many ways: it can signal for their degradation via the proteasome, alter their cellular location, affect their activity and promote or prevent protein interactions.[4][5][6] Ubiquitination is carried out in three main steps; activation, conjugation and ligation, performed by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). The result of this sequential cascade binds ubiquitin to lysine residues on the protein substrate via an isopeptide bond or to the amino group of the protein's N-terminus via a peptide bond.[7][8]

The protein modifications can either be a single ubiquitin protein or chains of ubiquitin. There are different forms of chains, named by which of the seven lysine amino acids are used to link the chain together. Lysine 48-linked chains, linked by the 48th amino acid (a lysine) have been well studied. They are the forms of chains that signal proteins to the proteasome which destroys and recycles proteins.[8] This discovery won the Nobel Prize for chemistry in 2004.[9][10] Lysine 63-linked chains, linked by the 63rd amino acid of ubiquitin (a lysine), regulate processes such as endocytic trafficking, inflammation, translation and DNA repair.[11]

Identification

Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975[1] as an 8.5 kDa protein of unknown function expressed in all eukaryotic cells. The basic functions of ubiquitin and the components of the ubiquitination pathway were elucidated in the early 1980s at the Technion by Aaron Ciechanover, Avram Hershko, and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004.[9]

The ubiquitination system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts. A heat-stable polypeptide present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme in an ATP- and Mg2+-dependent process.[12] Multiple APF-1 molecules were linked to a single substrate 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 lysine residues.

The protein

Ubiquitin properties (human)
Number of residues 76
Molecular mass 8564.8448 Da
Isoelectric point (pI) 6.79
Gene names RPS27A (UBA80, UBCEP1), UBA52 (UBCEP2), UBB, UBC
Sequence in amino acid abbreviations MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPD

QQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG

Ubiquitin is a small protein that exists in all eukaryotic cells. 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 acids and has a molecular mass of about 8.5 kDa. Key features include its C-terminal tail and the 7 lysine residues. It is highly conserved among eukaryotic species: Human and yeast ubiquitin share 96% sequence identity.

Genes

Ubiquitin is encoded in mammals by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins.[3]

Origins

No ubiquitin and ubiquitination machinery are known to exist in prokaryotes. However, ubiquitin is believed to have descended from prokaryotic proteins similar to ThiS[13] or MoaD.[14] These prokaryotic proteins, despite having little sequence identity (ThiS has 14% identity to ubiquitin), share the same protein fold. These proteins also share sulfur chemistry with ubiquitin. MoaD, which is involved in molybdenum cofactor biosynthesis, interacts with MoeB, which acts like an E1 ubiquitin-activating enzyme for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme ThiF. It is also believed that the Saccharomyces cerevisiae protein Urm-1, a ubiquitin-related modifier, is a "molecular fossil" that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.[15]

Ubiquitination

The ubiquitination system (showing a RING E3 ligase).

Ubiquitination (also known as ubiquitylation) is an enzymatic, post-translational modification (PTM) process in which a ubiquitin protein is attached to a substrate protein. This process most commonly binds the last amino acid of ubiquitin (glycine 76) to a lysine residue on the substrate. An isopeptide bond is formed between the carboxylic acid group of the ubiquitin's glycine and the epsilon amino group of the substrate's lysine.[16] Cases are known in which the amine group of a protein's N-terminus is used for ubiquitination, rather than a lysine residue.[17][18][19] In a few rare cases nonlysine residues have been identified as ubiquitination targets, such as cysteine, threonine and serine.[20][21] The end result of this process is the addition of one ubiquitin molecule (monoubiquitination) or a chain of ubiquitin molecules (polyubiquitination) to the substrate protein.[22]

Ubiquitination requires three types of enzymes; ubiquitin-activating enzymes, ubiquitin-conjugating enzymes and ubiquitin ligases, known as E1s, E2s and E3s, respectively. The process consists of three main steps:

  1. Activation: Ubiquitin is activated in a two-step reaction by an E1 ubiquitin-activating enzyme, which is dependent on ATP. The initial step involves production of a ubiquitin-adenylate intermediate. The E1 binds both ATP and ubiquitin and catalyses the acyl-adenylation of the C-terminus of the ubiqutin molecule. The second step transfers ubiquitin to an active site cysteine residue, with release of AMP. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group.[16][23] The human genome contains two genes that produce enzymes capable of activating ubiquitin; UBA1 and UBA6.[24]
  2. Conjugation: E2 ubiquitin-conjugating enzymes catalyse the transfer of ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. In order to perform this reaction, the E2 binds to both activated ubiquitin and the E1 enzyme. Humans possess 35 different E2 enzymes, whereas other eukaryotic organisms have between 16 and 35. They are characterised by their highly conserved structure; known as the ubiquitin-conjugating catalytic (UBC) fold.[25]
    Glycine and lysine linked by an isopeptide bond. The isopeptide bond is highlighted yellow.
  3. Ligation: E3 ubiquitin ligases catalyse the final step of the ubiquitination cascade. Most commonly they create 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 E3s. E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and substrate. Some E3 enzymes also activate the E2 enzymes. E3 enzymes possess one of two domains: the homologous to the E6-AP carboxyl terminus (HECT) domain and the really interesting new gene (RING) domain (or the closely related U-box domain). HECT domain E3s transiently bind ubiquitin in this process, whereas RING domain E3s catalyse the direct transfer from the E2 enzyme to the substrate.[26] The anaphase-promoting complex (APC) and the SCF complex (for Skp1-Cullin-F-box protein complex) are two examples of multi-subunit E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome.[27]

In the ubiquitination cascade, E1 can bind with many E2s, which can bind with hundreds of E3s in a hierarchical way. Having levels within the cascade allows tight regulation of the ubiquitination machinary.[7] Other ubiquitin-like proteins (UBLs) are also modified via the E1–E2–E3 cascade, although variations in these systems do exist.[28]

Variety of ubiquitin modifications

Ubiquitination affects cellular process by regulating the degradation of proteins (via the proteasome and lysosome); coordinating the cellular localisation of proteins; activating and inactivating proteins; and modulating protein-protein interactions.[4][5][6] These effects are mediated by different types of substrate ubiquitination, for example the addition of a single ubiquitin molecule (monoubiquitination) or different types of ubiqutin chains (polyubiquitination).[29]

Monoubiquitination

Monoubiquitination is the addition of one ubiquitin molecule to one substrate protein residue. Multi-monoubiquitination is the addition of one ubiquitin molecule to multiple substrate residues. The monoubiquitination of a protein can have different effects to the polyubiquitination of the same protein. The addition of a single ubiquitin molecule is thought to be required prior to the formation of polyubiquitin chains.[29] Monoubiquitination affects cellular processes such as membrane trafficking, endocytosis and viral budding.[11][30]

Polyubiquitin chains

Diagram of lysine 48-linked diubiquitin.The linkage between the two ubiquitin chains is shown in orange.
Diagram of lysine 63-linked diubiquitin. The linkage between the two ubiquitin chains is shown in orange.

Polyubiquitination is the formation of a ubiquitin chain on a single lysine residue on the substrate protein. Following addition of a single ubiquitin moiety to a protein substrate, further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain.[29] These chains are made by linking the glycine residue of a ubiquitin molecule to a lysine of ubiquitin bound to a substrate. Ubiquitin has seven lysine residues and an N-terminus that may serve as points of ubiquitination, they are K6, K11, K27, K29, K33, K48 and K63. Lysine 48-linked chains were the first identified and are the best characterised type of ubiquitin chain. K63 chains have also been well characterised, whereas the function of other lysine chains, mixed chains, branched chains, N-terminal linear chains and heterologous chains (mixtures of ubiquitin and other ubiquitin like proteins) remains more unclear.[29][30][31][32][33]

Lysine 48-linked polyubiquitin chains target proteins for destruction, by a process known as proteolysis. At least four ubiquitin molecules must be attached to a lysine residue on the condemned protein in order for it to be recognised by the 26S proteasome.[34] This is a barrel-shaped structure comprising a central proteolytic core made of four ring structures, flanked by two cylinders that selectively allow entry of ubiquitinated proteins. Once inside, the proteins are rapidly degraded into small peptides (usually 3–25 amino acid residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use.[35] Although the majority of proteasomal substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.[36] The polyubiquitin chains are recognised by a subunit of the proteasome; S5a/Rpn10. This is achieved by a ubiquitin interacting motif (UIM) found in a hydrophobic patch in the C-terminal region of the S5a/Rpn10 unit.[4]

Lysine 63-linked chains are not associated with proteasomal degradation of the substrate protein. Instead they allow the coordination of other processes such as endocytic trafficking, inflammation, translation and DNA repair.[11] In cells lysine 63-linked chains are bound by the ESCRT-0 complex, which prevents their binding to the proteasome. This complex contains two proteins, Hrs and STAM1, that contain a UIM which allows it to bind to lysine 63-linked chains.[37][38]

Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains.[30] There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and N-terminal chains can induce proteasomal degradation.[36][39]

Branched ubiquitin chains containing multiple linkage types can be formed.[40] The function of these chains is unknown.[8]

Structure of chains

Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. Lysine 63-linked and N-terminal chains produce fairly linear chains known as open conformation chains. Lysine 6-, 11- and 48-linked chains form closed conformations. The ubiquitin molecules in linear chains do not interact with each other, except for the covalent isopeptide bonds linking them together. In contrast, the closed conformation chains have interfaces with interacting residues. Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage. The proteins that bind ubiquitin have ubiquitin binding domains (UBDs). The distances between individual ubiquitin units in chains differ between lysine 63- and 48- linked chains. The UBDs exploit this by having small spacers between ubiquitin interacting motifs that bind lysine 48-linked chains (compact ubiquitin chains) and larger spacers for lysine 63-linked chains. The machinery involved in recognising polyubiquitin chains can also differentiate between the linear lysine 63-linked chains and linear N-terminal chains, demonstrated by the fact that the latter can induce proteasomal degradation of the substrate.[8][11][39]

Functions of ubiquitin modification

The ubiquitination system functions in a wide variety of cellular processes, including:[41]

  • 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

Membrane proteins

Multi-monoubiquitination can mark transmembrane proteins (for example, receptors) for removal from membranes (internalisation) and fulfil several signalling roles within the cell. When cell-surface transmembrane molecules are tagged with ubiquitin, the subcellular localization of the protein is altered, often targeting the protein for destruction in lysosomes. This serves as a negative feedback mechanism because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation. Like monoubiquitination, lysine 63-linked polyubiquitin chains also has a role in the trafficking some membrane proteins.[11][29][34]

Genomic maintenance

Proliferating cell nuclear antigen (PCNA) is a protein involved in DNA synthesis. Under normal physiological conditions PCNA is sumoylated (a similar post-translational modification to ubiquitination). When DNA is damaged by ultra-violet radiation or chemicals, the SUMO molecule that is attached to a lysine residue is replaced by ubiquitin. Monoubiquitinated PCNA recruits polymerases that can carry out DNA synthesis with damaged DNA; but this is very error-prone, possibly resulting in the synthesis of mutated DNA. Lysine 63-linked polyubiquitination of PCNA allows it to perform a less error prone mutation bypass known by the template switching pathway.[6][42][43]

Ubiquitination of histone H2AX is involved in DNA damage recognition of DNA double-strand breaks. Lysine 63-linked polyubiquitin chains are formed on H2AX histone by the E2/E3 ligase pair, Ubc13-Mms2/RNF168.[44][45] This K63 chain appears to recruit RAP80, which contains a UIM, and RAP80 then helps localize BRCA1. This pathway will eventually recruit the necessary proteins for homologous recombination repair.[46]

Transcriptional regulation

Histones can be ubiquitinated and this is usually in the form of monoubiquitination (although polyubiquitinated forms do occur). Histone ubiquitination alters chromatin structure and allows the access of enzymes involved in transcription. Ubiquitin on histones also acts a binding site for proteins that either activate or inhibit transcription and also can induce further post-translational modifications of the protein. These effects can all modulate the transcription of genes.[47][48]

Deubiquitination

Deubiquitinating enzymes (DUBs) oppose the role of ubiquination by removing ubiquitin from substrate proteins. They are cysteine proteases that cleave the amide bond between the two proteins. They are highly specific, as are the E3 ligases that attach the ubiquitin, with only a few substrates per enzyme. They can cleave both isopeptide (between ubiquitin and lysine) and peptide bonds (between ubiquitin and the N-terminus). In addition to removing ubiquitin from substrate proteins, DUBs have many other roles within the cell. Ubiquitin is expressed either as multiple copies joined in a chain (polyubiquitin) or attached to ribosomal subunits. DUBs cleave these proteins to produce active ubiquitin. They also recycle ubiquitin that has been accidentally bound to small nucleophilic molecules during the ubiquitination process. Monoubiquitin is formed by DUBs that cleave ubiquitin from free polyubiquitin chains that have been previously removed from proteins.[49][50]

Ubiquitin binding domains

Table of characterized Ubiquitin-binding domains[51]
Domain Number of Proteins

in Proteome

Length

(amino acids)

Ubiquitin Binding

Affinity

CUE S. cerevisiae 7

H. sapiens 21

42–43 ~2–160 μM
GATII S. cerevisiae 2

H. sapiens 14

135 ~180 μM
GLUE S. cerevisiae ?

H. sapiens ?

~135 ~460 μM
NZF S. cerevisiae 1

H. sapiens 25

~35 ~100–400 μM
PAZ S. cerevisiae 5

H. sapiens 16

~58 Not known
UBA S. cerevisiae 10

H. sapiens 98

45–55 ~0.03-500 μM
UEV S. cerevisiae 2

H. sapiens ?

~145 ~100–500 μM
UIM S. cerevisiae 8

H. sapiens 71

~20 ~100–400 μM
VHS S. cerevisiae 4

H. sapiens 28

150 Not known

redirect Ubiquitin Binding Domains

Ubiquitin-binding domains (UBDs) are modular protein domains that non-covalently bind to ubiquitin, these motifs control various cellular events. Detailed molecular structures are known for a number of UBDs, binding specificity determines their mechanism of action and regulation, and how it regulates cellular proteins and processes.[51]

Disease associations

Pathogenesis

The ubiquitin pathway has been implicated in the pathogenesis of several diseases and genetic disorders:

Diagnostic use

Immunohistochemistry using antibodies to ubiquitin can identify abnormal accumulations of this protein inside cells, indicating a disease process. These protein accumulations are referred to as inclusion bodies (which is a general term for any microscopically visible collection of abnormal material in a cell). Examples include:

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),[55] ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe).[56][57] 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 "ubiquitin fold" or sometimes called ubiquiton fold. FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a 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.[41]

Within some species, the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria's disposal after fertilization occurs.[58]

Prokaryotic ubiquitin-like protein (Pup)

Recently, a functional analog of ubiquitin has been found in prokaryotes. Prokaryotic ubiquitin-like protein (Pup) serves the same function (targeting proteins for degradations), although the enzymology of ubiquitination and pupylation is different. In contrast to the three-step reaction of ubiquitination, pupylation requires two steps, therefore only two enzymes are involved in pupylation.

Human proteins containing ubiquitin domain

ANUBL1; BAG1; BAT3/BAG6; DDI1; DDI2; FAU; HERPUD1; HERPUD2; HOPS; IKBKB; ISG15; LOC391257; MIDN; NEDD8; OASL; PARK2; RAD23A; RAD23B; RPS27A; SACS; 8U SF3A1; SUMO1; SUMO2; SUMO3; SUMO4; TMUB1; TMUB2; UBA52; UBB; UBC; UBD; UBFD1; UBL4; UBL4A; UBL4B; UBL7; UBLCP1; UBQLN1; UBQLN2; UBQLN3; UBQLN4; UBQLNL; UBTD1; UBTD2; UHRF1; UHRF2;

Related proteins

Prediction of ubiquitination

Currently available prediction programs are:

  • UbiPred is a SVM-based prediction server using 31 physicochemical properties for predicting ubiquitination sites.[59]
  • UbPred is a random forest-based predictor of potential ubiquitination sites in proteins. It was trained on a combined set of 266 non-redundant experimentally verified ubiquitination sites available from our experiments and from two large-scale proteomics studies.[60]
  • CKSAAP_UbSite is SVM-based prediction which employs the composition of k-spaced amino acid pairs surrounding a query site (i.e. any lysine in a query sequence) as input, usess the same dataset as UbPred.[61]

See also

References

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  35. ^ Lecker SH, Goldberg AL, Mitch WE (July 2006). "Protein degradation by the ubiquitin-proteasome pathway in normal and disease states". J. Am. Soc. Nephrol. 17 (7): 1807–19. doi:10.1681/ASN.2006010083. PMID 16738015. 
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  38. ^ Bache KG, Raiborg C, Mehlum A, Stenmark H (April 2003). "STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes". J. Biol. Chem. 278 (14): 12513–21. doi:10.1074/jbc.M210843200. PMID 12551915. 
  39. ^ a b Zhao S, Ulrich HD (April 2010). "Distinct consequences of posttranslational modification by linear versus K63-linked polyubiquitin chains". Proc. Natl. Acad. Sci. U.S.A. 107 (17): 7704–9. doi:10.1073/pnas.0908764107. PMC 2867854. PMID 20385835. 
  40. ^ Kim HT, Kim KP, Lledias F, Kisselev AF, Scaglione KM, Skowyra D, Gygi SP, Goldberg AL (June 2007). "Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages". J. Biol. Chem. 282 (24): 17375–86. doi:10.1074/jbc.M609659200. PMID 17426036. 
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  42. ^ Shaheen M, Shanmugam I, Hromas R (2010). "The Role of PCNA Posttranslational Modifications in Translesion Synthesis". J Nucleic Acids 2010: 1. doi:10.4061/2010/761217. PMC 2935186. PMID 20847899. 
  43. ^ Jackson SP, Durocher D (March 2013). "Regulation of DNA damage responses by ubiquitin and SUMO". Mol. Cell 49 (5): 795–807. doi:10.1016/j.molcel.2013.01.017. PMID 23416108. 
  44. ^ Campbell SJ, Edwards RA, Leung CC, et al. (July 2012). "Molecular insights into the function of RING finger (RNF)-containing proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation". J. Biol. Chem. 287 (28): 23900–10. doi:10.1074/jbc.M112.359653. PMC 3390666. PMID 22589545. 
  45. ^ Ikura T, Tashiro S, Kakino A, et al. (October 2007). "DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics". Mol. Cell. Biol. 27 (20): 7028–40. doi:10.1128/MCB.00579-07. PMC 2168918. PMID 17709392. 
  46. ^ Kim H, Chen J, Yu X (May 2007). "Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response". Science 316 (5828): 1202–5. doi:10.1126/science.1139621. PMID 17525342. 
  47. ^ Hofmann K (April 2009). "Ubiquitin-binding domains and their role in the DNA damage response". DNA Repair (Amst.) 8 (4): 544–56. doi:10.1016/j.dnarep.2009.01.003. PMID 19213613. 
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External links

Programs for ubiquitination prediction:

Academic

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Ubiquitin family Provide feedback

This family contains a number of ubiquitin-like proteins: SUMO (smt3 homologue) (see Q02724), Nedd8 (see P29595), Elongin B (see Q15370), Rub1 (see Q9SHE7), and Parkin (see O60260). A number of them are thought to carry a distinctive five-residue motif termed the proteasome-interacting motif (PIM), which may have a biologically significant role in protein delivery to proteasomes and recruitment of proteasomes to transcription sites [5].

Literature references

  1. Vijay-Kumar S, Bugg CE, Cook WJ; , J Mol Biol 1987;194:531-544.: Structure of ubiquitin refined at 1.8 A resolution. PUBMED:3041007 EPMC:3041007

  2. Cook WJ, Jeffrey LC, Kasperek E, Pickart CM; , J Mol Biol 1994;236:601-609.: Structure of tetraubiquitin shows how multiubiquitin chains can be formed. PUBMED:8107144 EPMC:8107144

  3. Bayer P, Arndt A, Metzger S, Mahajan R, Melchior F, Jaenicke R, Becker J; , J Mol Biol 1998;280:275-286.: Structure determination of the small ubiquitin-related modifier SUMO-1. PUBMED:9654451 EPMC:9654451

  4. Whitby FG, Xia G, Pickart CM, Hill CP; , J Biol Chem 1998;273:34983-34991.: Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes. PUBMED:9857030 EPMC:9857030

  5. Upadhya SC, Hegde AN; , Trends Biochem Sci 2003;28:280-283.: A potential proteasome-interacting motif within the ubiquitin-like domain of parkin and other proteins. PUBMED:12826399 EPMC:12826399


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000626

Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1, INTERPRO), a ubiquitin-conjugating enzyme (E2, INTERPRO), and a ubiquitin ligase (E3, INTERPRO, INTERPRO), which work sequentially in a cascade. There are many different E3 ligases, which are responsible for the type of ubiquitin chain formed, the specificity of the target protein, and the regulation of the ubiquitinylation process [PUBMED:12646216]. Ubiquitinylation is an important regulatory tool that controls the concentration of key signalling proteins, such as those involved in cell cycle control, as well as removing misfolded, damaged or mutant proteins that could be harmful to the cell. Several ubiquitin-like molecules have been discovered, such as Ufm1 (INTERPRO), SUMO1 (INTERPRO), NEDD8, Rad23 (INTERPRO), Elongin B and Parkin (INTERPRO), the latter being involved in Parkinson's disease [PUBMED:15564047].

Ubiquitin is a protein of 76 amino acid residues, found in all eukaryotic cells and whose sequence is extremely well conserved from protozoan to vertebrates. Ubiquitin acts through its post-translational attachment (ubiquitinylation) to other proteins, where these modifications alter the function, location or trafficking of the protein, or targets it for destruction by the 26S proteasome [PUBMED:15454246]. The terminal glycine in the C-terminal 4-residue tail of ubiquitin can form an isopeptide bond with a lysine residue in the target protein, or with a lysine in another ubiquitin molecule to form a ubiquitin chain that attaches itself to a target protein. Ubiquitin has seven lysine residues, any one of which can be used to link ubiquitin molecules together, resulting in different structures that alter the target protein in different ways. It appears that Lys(11)-, Lys(29) and Lys(48)-linked poly-ubiquitin chains target the protein to the proteasome for degradation, while mono-ubiquitinylated and Lys(6)- or Lys(63)-linked poly-ubiquitin chains signal reversible modifications in protein activity, location or trafficking [PUBMED:14998368]. For example, Lys(63)-linked poly-ubiquitinylation is known to be involved in DNA damage tolerance, inflammatory response, protein trafficking and signal transduction through kinase activation [PUBMED:15556404]. In addition, the length of the ubiquitin chain alters the fate of the target protein. Regulatory proteins such as transcription factors and histones are frequent targets of ubquitinylation [PUBMED:15525528].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Ubiquitin (CL0072), which has the following description:

This family includes proteins that share the ubiquitin fold. It currently unites four SCOP superfamilies.

The clan contains the following 41 members:

APG12 Atg8 Blt1 Caps_synth_GfcC CIDE-N Cobl DUF1315 DUF2407 DUF4430 DWNN FERM_N Lambda_tail_I Multi_ubiq NQRA_SLBB PB1 PI3K_rbd Plug Prok_Ub RA Rad60-SLD Rad60-SLD_2 Ras_bdg_2 RBD SLBB Telomere_Sde2 TGS ThiS ThiS-like TmoB TUG-UBL1 Ub-Mut7C Ub-RnfH ubiquitin Ubiquitin_2 Ubiquitin_3 UBX Ufm1 UN_NPL4 Urm1 YchF-GTPase_C YukD

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(76)
Full
(11560)
Representative proteomes NCBI
(11456)
Meta
(369)
RP15
(2304)
RP35
(3483)
RP55
(4906)
RP75
(6203)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(76)
Full
(11560)
Representative proteomes NCBI
(11456)
Meta
(369)
RP15
(2304)
RP35
(3483)
RP55
(4906)
RP75
(6203)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(76)
Full
(11560)
Representative proteomes NCBI
(11456)
Meta
(369)
RP15
(2304)
RP35
(3483)
RP55
(4906)
RP75
(6203)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD, Griffiths-Jones SR
Number in seed: 76
Number in full: 11560
Average length of the domain: 67.10 aa
Average identity of full alignment: 44 %
Average coverage of the sequence by the domain: 28.05 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.6 21.6
Trusted cut-off 21.6 21.6
Noise cut-off 21.5 21.5
Model length: 69
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 16 interactions for this family. More...

zf-UBP UBACT Peptidase_C48 UBA_e1_thiolCys CUE zf-A20 UIM Vps36_ESCRT-II ubiquitin Peptidase_C12 UDG UBA UQ_con SH3_1 UCH ThiF

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the ubiquitin domain has been found. There are 508 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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