
1202  structures 868  species 80  interactions 21402  sequences 541  architectures

Family: ubiquitin (PF00240)

Summary: Ubiquitin family


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Ubiquitin Edit Wikipedia article

Not to be confused with Ubiquinol.
Ubiquitin family
Ubiquitin cartoon-2-.png
A diagram of ubiquitin. The seven lysine sidechains are shown in yellow/orange.
Symbol ubiquitin
Pfam PF00240
InterPro IPR000626
SCOP 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] in Israel by Gideon Goldstein and further characterized throughout the 1970s and 1980s.[2] There are four genes in the human genome that produce ubiquitin: UBB, UBC, UBA52 and RPS27A.[3]

The addition of ubiquitin to a substrate protein is called ubiquitination or ubiquitylation. Ubiquitination 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), respectively. The result of this sequential cascade binds ubiquitin to lysine residues on the protein substrate via an isopeptide bond, cysteine residues through a thioester bond, serine and threonine residues through an ester bond, or the amino group of the protein's N-terminus via a peptide bond.[7][8][9]

The protein modifications can be either a single ubiquitin protein (monoubiquitination) or a chain of ubiquitin (polyubiquitination). The ubiquitination bonds are always formed with one of the seven lysine residues as well as the very N-terminal methionine from the ubiquitin molecule. These 'linking' residues are represented by a "K" or "M" (which is the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule. First, a ubiquitin molecule is bonded by its C-terminus to a specific lysine residue on the target protein. Poly-ubiquitination occurs when the C-terminus of another ubiquitin, will be linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule itself (for example on K48, K29 or M1), forming a chain. This process repeats several times, leading to the addition of several ubiquitins. Only poly-ubiquitination on defined lysines, mostly on K48 and K29, is related to degradation by the proteasome (referred to as the "molecular kiss of death"), while other polyubiquitinations (e.g. on K63, K11, K6 and M1) and monoubiquitinations may regulate processes such as endocytic trafficking, inflammation, translation and DNA repair.[10]

The discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the Nobel Prize in chemistry in 2004.[8][11][12]


Surface representation of Ubiquitin.



The protein

Ubiquitin properties (human)
Number of residues 76
Molecular mass 8564.8448 Da
Isoelectric point (pI) 6.79








The ubiquitination system (showing a RING E3 ligase).

Ubiquitination (or ubiquitylation) is an enzymatic post-translational modification 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 carboxyl group (COO) of the ubiquitin's glycine and the epsilon-amino group (ε-NH+
) of the substrate's lysine.[17] Trypsin cleavage of a ubiquitin-conjugated substrate leaves a di-glycine "remnant" that is used to identify the site of ubiquitination.[18][19] Ubiquitin can also be bound to other sites in a protein which are electron-rich nucleophiles, termed "non-canonical ubiquitination".[9] This was first observed with the amine group of a protein's N-terminus being used for ubiquitination, rather than a lysine residue, in the protein MyoD[20] and has been observed since in 22 other proteins in multiple species,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][22][38][39] including ubiquitin itself.[40][41] There is also increasing evidence for nonlysine residues as ubiquitination targets using non-amine groups, such as the sulfhydryl group on cysteine,[36][37][42][43][44][45][46][47][48][49] and the hydroxyl group on threonine and serine.[36][37][42][48][49][50][51][52][53] 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.[54]


  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 ubiquitin 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.[17][55] The human genome contains two genes that produce enzymes capable of activating ubiquitin: UBA1 and UBA6.[56]
  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.[57]


E4 enzymes, or ubiquitin-chain elongation factors, are capable of adding pre-formed polyubiquitin chains to substrate proteins.[61] For example, multiple monoubiquitylation of the tumor suppressor p53 by Mdm2[62] can be followed by addition of a polyubiquitin chain using p300 and CBP.[63][64]


Ubiquitination affects cellular process by regulating the degradation of proteins (via the proteasome and lysosome), coordinating the cellular localization 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 ubiquitin chains (polyubiquitination).[65]


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.[65] Monoubiquitination affects cellular processes such as membrane trafficking, endocytosis and viral budding.[10][66]

Polyubiquitin chains


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.[65] 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 serves as points of ubiquitination; they are K6, K11, K27, K29, K33, K48, K63 and M1, respectively.[8] 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, M1-linked linear chains, and heterologous chains (mixtures of ubiquitin and other ubiquitin-like proteins) remains more unclear.[19][41][65][66][67]

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.[68] This is a barrel-shape 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.[69] Although the majority of protein substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.[70] 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.[10] 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.[71][72]

Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains.[66] There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and methionine 1 can induce proteasomal degradation.[70][73]

Branched ubiquitin chains containing multiple linkage types can be formed.[74] The function of these chains is unknown.[8]


Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. K29-, K33-,[75] K63- and M1-linked chains have a fairly linear conformation; they are known as open-conformation chains. K6-, K11-, and K48-linked chains form closed conformations. The ubiquitin molecules in open-conformation 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. Proteins can specifically bind to ubiquitin via 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 K63-linked chains and M1-linked chains, demonstrated by the fact that the latter can induce proteasomal degradation of the substrate.[8][10][73]


The ubiquitination system functions in a wide variety of cellular processes, including:[76]

Membrane proteins


Genomic maintenance


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.[79][80] 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.[81]

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 as 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.[82][83]



Ubiquitin-binding domains

Table of characterized Ubiquitin-binding domains[86]
Domain Number of Proteins

in Proteome


(amino acids)

Ubiquitin Binding


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


Disease associations



Diagnostic use


Link to cancer

Post-translational modification of proteins is a generally used mechanism in eukaryotic cell signaling.[91] Ubiquitination, or ubiquitin conjugation to proteins, is a crucial process for cell cycle progression and cell proliferation and development. Although ubiquitination usually serves as a signal for protein degradation through the 26S proteasome, it could also serve for other fundamental cellular processes[91], e.g. in endocytosis[92], enzymatic activation[93] and DNA repair.[94] Moreover, since ubiquitination functions to tightly regulate the cellular level of cyclins, its misregulation is highly expected to have severe impacts. First evidence of the importance of the ubiquitin/proteasome pathway in oncogenic processes was observed due to the high antitumor activity of proteasome inhibitors.[95][96][97] Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or presence in human carcinoma.[98][99][100][101][102][103][104][105] Malignancies could be developed through loss of function mutation directly at the tumor suppressor gene, increased activity of ubiquitination, and/or indirect attenuation of ubiquitination due to mutation in related proteins.[106]

Direct loss of function mutation of E3 ubiquitin ligase

Renal cell carcinoma

The VHL (Von Hippel–Lindau) gene encodes a component of an E3 Ubiquitin Ligase. VHL complex targets member of the hypoxia-inducible transcription factor family (HIF) for degradation by interacting with the oxygen-dependent destruction domain under normoxic condition. HIF activates downstream targets such as the vascular endothelial growth factor (VEGF), promoting angiogenesis. Mutations in VHL prevent degradation of HIF and thus lead to the formation of hypervascular lesions and renal tumors.[98][106]

Breast cancer

The BRCA1 gene is another tumor suppressor gene in human which encodes the BRCA1 protein that is involved in response to DNA damage. The protein contains a RING motif with E3 Ubiquitin Ligase activity. BRCA1 could form dimer with other molecules, such as BARD1 and BAP1, for its ubiquitination activity. Mutations that affect the ligase function are often found and associated with various cancers.[102][106]

Cyclin E

As processes in cell cycle progression is the most fundamental processes for cellular growth and differentiation, and are the most common to be altered in human carcinomas, it is expected for cell cycle-regulatory proteins to be under tight regulation. The level of cyclins, as the name suggests, are high only at certain time point during cell cycle. This is achieved by continuous controlled of cyclins/CDKs level through ubiquitination and degradation. When cyclin E is partnered with CDK2 and get phosphorylated, an SCF-associated F-box protein Fbw7 recognizes the complex and thus target it for degradation. Mutations in Fbw7 have been found in more than 30% of human tumors, characterizing is as a tumor suppressor protein.[105]

Increased ubiquitination activity

Cervical cancer

Oncogenic types of the human papillomavirus (HPV) are known to hijack cellular ubiquitin-proteasome pathway for viral infection and replication. The E6 proteins of HPV will bind to the N-terminus of the cellular E6-AP E3 ubiquitin ligase, redirecting the complex to bind p53, a well-known tumor suppressor gene that inactivation is found in many types of cancer.[100] Thus, p53 undergoes ubiquitination and proteasome-mediated degradation. Meanwhile E7, another one of the early-expressed HPV genes, will bind to Rb, also a tumor suppressor gene, mediating its degradation.[106] The loss of p53 and Rb in cells allows limitless cell proliferation to occur.

p53 regulation

Gene amplification often occur in various tumor cases, including of MDM2, a gene encodes for a RING E3 Ubiquitin ligase responsible for downregulation of p53 activity. MDM2 targets p53 for ubiquitination and proteasomal degradation thus keeping its level appropriate for normal cell condition. Overexpression of MDM2 causes loss of p53 activity and therefore allowing cells to have a limitless replicative potential.[101][106]


Another gene that is a target of gene amplification is SKP2. SKP2 is an F-box protein that roles in substrate recognition for ubiquitination and degradation. SKP2 targets p27Kip-1, an inhibitor of cyclin-dependent kinases (CDKs). CDKs2/4 partner with the cyclinsE/D, respectively, family of cell cycle regulator to control cell cycle progression through the G1 phase. Low level of p27Kip-1 protein is often found in various cancers and is due to overactivation of ubiquitin-mediated proteolysis through overexpression of SKP2.[103][106]


Efp, or estrogen-inducible RING-finger protein, is an E3 ubiquitin ligase that overexpression has been shown to be the major cause of estrogen-independent breast cancer.[97][107] Efp's substrate is 14-3-3 protein which negatively regulates cell cycle.

Evasion of Ubiquitination

Colorectal cancer

The gene associated with colorectal cancer is the adenomatous polyposis coli (APC), which is a classic tumor suppressor gene. APC gene product targets beta-catenin for degradation via ubiquitination at the N-terminus, thus regulating its cellular level. Most colorectal cancer cases are found with mutations in the APC gene. However, in cases where APC gene is not mutated, mutations are found in the N-terminus of beta-catenin which renders it ubiquitination-free and thus increased activity.[99][106]


As the most aggressive cancer originated in the brain, mutations found in patients with glioblastoma are related to the deletion of a part of the extracellular domain of the epidermal growth factor receptor (EGFR). This deletion causes CBL E3 ligase unable to bind the receptor for its recycling and degradation via a ubiquitin-lysosomal pathway. Thus, EGFR is constitutively active in the cell membrane and activates its downstream effectors that are involved in cell proliferation and migration.[104]

Phosphorylation-dependent ubiquitination

The interplay between ubiquitination and phosphorylation has been an ongoing research interest since phosphorylation often serves as a marker where ubiquitination leads to degradation.[91] Moreover, ubiquitination can also act to turn on/off the kinase activity of a protein.[108] The critical role of phosphorylation is largely underscored in the activation and removal of autoinhibition in Cbl protein.[109] Cbl is an E3 ubiquitin ligase with a RING finger domain that interacts with its tyrosine kinase binding (TKB) domain, preventing interaction of the RING domain with an E2 ubiquitin-conjugating enzyme. This intramolecular interaction is an autoinhibition regulation that prevents its role as a negative regulator of various growth factors and tyrosine kinase signaling and T-cell activation.[109] Phosphorylation of Y363 relieves the autoinhibition and enhances binding to E2.[109] Mutations that renders the Cbl protein dysfunctional due to the loss of its ligase/tumor suppressor function and maintenance of its positive signaling/oncogenic function have been shown to cause development of cancer.[110][111]

As a drug target

Screening for ubiquitin ligase substrates

Identification of E3 ligase substrates is critical to understand its implication in human diseases since deregulation of E3-substrate interactions are often served as major cause in many. To overcome the limitation of mechanism used to identify the substrates of the E3 Ubiquitin Ligase, a system called the 'Global Protein Stability (GPS) Profiling' was developed in 2008.[112] This high-throughput system made use of reporter proteins fused with thousands of potential substrates independently. By inhibition of the ligase activity (through the making of Cul1 dominant negative thus renders ubiquitination not to occur), increased reporter activity shows that the identified substrates are being accumulated. This approach added a large number of new substrates to the list of E3 ligase substrates.

Possible therapeutic appllications

Blocking of specific substrate recognition by the E3 ligases, e.g. Bortezomib.[107]


Finding a specific molecule that selectively inhibits the activity of a certain E3 ligase and/or the protein-protein interactions implicated in the disease remains as one of the important and expanding research area. Moreover, as ubiquitination is a multi-step process with various players and intermediate forms, consideration of the much complex interactions between components needs to be taken heavily into account while designing the small molecule inhibitors.[97]

Ubiquitin-like modifiers





Prokaryotic ubiquitin-like protein (Pup)


Human proteins containing ubiquitin domain


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.[117]
  • CKSAAP_UbSite is SVM-based prediction that employs the composition of k-spaced amino acid pairs surrounding a query site (i.e. any lysine in a query sequence) as input, uses the same dataset as UbPred.[119]

See also


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External links



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

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000626

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].

Ubiquitin is a globular protein, the last four C-terminal residues (Leu-Arg-Gly-Gly) extending from the compact structure to form a 'tail', important for its function. The latter is mediated by the covalent conjugation of ubiquitin to target proteins, by an isopeptide linkage between the C-terminal glycine and the epsilon amino group of lysine residues in the target proteins.

This entry represents a domain characteristic of ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as SUMO [PUBMED:17491593, PUBMED:15479240] and Nedd8 [PUBMED:9857030].

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Curation and family details


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Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD, Griffiths-Jones SR
Number in seed: 63
Number in full: 21402
Average length of the domain: 70.30 aa
Average identity of full alignment: 37 %
Average coverage of the sequence by the domain: 25.31 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
Model details:
Parameter Sequence Domain
Gathering cut-off 25.4 21.2
Trusted cut-off 25.4 21.2
Noise cut-off 25.3 21.1
Model length: 72
Family (HMM) version: 22
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Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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 1202 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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