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1954  structures 1726  species 0  interactions 53635  sequences 1033  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 yellow/orange.

Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975[1] by Gideon Goldstein and further characterized throughout the late 1970s and 1980s.[2] Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.[3]

The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation). Ubiquitylation affects proteins in many ways: it can mark them for degradation via the proteasome, alter their cellular location, affect their activity, and promote or prevent protein interactions.[4][5][6] Ubiquitylation involves 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 is to bind 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 (monoubiquitylation) or a chain of ubiquitin (polyubiquitylation). Secondary ubiquitin molecules are always linked to one of the seven lysine residues or the N-terminal methionine of the previous ubiquitin molecule. These 'linking' residues are represented by a "K" or "M" (the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule as in K48, K29 or M1. The first ubiquitin molecule is covalently bound through its C-terminal carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein. Polyubiquitylation occurs when the C-terminus of another ubiquitin is linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule, creating a chain. This process repeats several times, leading to the addition of several ubiquitins. Only polyubiquitylation 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 polyubiquitylations (e.g. on K63, K11, K6 and M1) and monoubiquitylations 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.

Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975[1] as an 8.6 kDa protein expressed in all eukaryotic cells. The basic functions of ubiquitin and the components of the ubiquitylation 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.[11]

The ubiquitylation 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.[13] 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)[which?]
Number of residues 76
Molecular mass 8564.8448 Da
Isoelectric point (pI) 6.79
Gene names RPS27A (UBA80, UBCEP1), UBA52 (UBCEP2), UBB, UBC
Sequence (single-letter)



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 8.6 kDa. Key features include its C-terminal tail and the 7 lysine residues. It is highly conserved throughout eukaryote evolution; human and yeast ubiquitin share 96% sequence identity.[citation needed]


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]


The ubiquitylation system (showing a RING E3 ligase).

Ubiquitylation (also known as ubiquitination or ubiquitinylation) 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.[14] Trypsin cleavage of a ubiquitin-conjugated substrate leaves a di-glycine "remnant" that is used to identify the site of ubiquitylation.[15][16] Ubiquitin can also be bound to other sites in a protein which are electron-rich nucleophiles, termed "non-canonical ubiquitylation".[9] This was first observed with the amine group of a protein's N-terminus being used for ubiquitylation, rather than a lysine residue, in the protein MyoD[17] and has been observed since in 22 other proteins in multiple species,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] including ubiquitin itself.[37][38] There is also increasing evidence for nonlysine residues as ubiquitylation targets using non-amine groups, such as the sulfhydryl group on cysteine,[33][34][39][40][41][42][43][44][45][46] and the hydroxyl group on threonine and serine.[33][34][39][45][46][47][48][49][50] The end result of this process is the addition of one ubiquitin molecule (monoubiquitylation) or a chain of ubiquitin molecules (polyubiquitination) to the substrate protein.[51]

Ubiquitination requires three types of enzyme: 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 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.[14][52] The human genome contains two genes that produce enzymes capable of activating ubiquitin: UBA1 and UBA6.[53]
  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.[54]
    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 (an obligate thioester intermediate is formed with the active-site cysteine of the E3), whereas RING domain E3s catalyse the direct transfer from the E2 enzyme to the substrate.[55] 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.[56]

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 machinery.[7] Other ubiquitin-like proteins (UBLs) are also modified via the E1–E2–E3 cascade, although variations in these systems do exist.[57]

E4 enzymes, or ubiquitin-chain elongation factors, are capable of adding pre-formed polyubiquitin chains to substrate proteins.[58] For example, multiple monoubiquitylation of the tumor suppressor p53 by Mdm2[59] can be followed by addition of a polyubiquitin chain using p300 and CBP.[60][61]


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).[62]


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.[62] Monoubiquitination affects cellular processes such as membrane trafficking, endocytosis and viral budding.[10][63]

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.[62] 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.[16][38][62][63][64]

Lysine 48-linked polyubiquitin chains target proteins for destruction, by a process known as proteolysis. Multi-ubiquitin chains at least four ubiquitin molecules long must be attached to a lysine residue on the condemned protein in order for it to be recognised by the 26S proteasome.[65] 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.[66] Although the majority of protein substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.[67] 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.[68][69]

Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains.[63] There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and methionine 1 can induce proteasomal degradation.[67][70]

Branched ubiquitin chains containing multiple linkage types can be formed.[71] 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-,[72] 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][70]


The ubiquitination system functions in a wide variety of cellular processes, including:[73]

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.[10][62][65][75]

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][76][77]

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.[78][79] 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.[80]

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.[81][82]


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 either expressed 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 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.[83][84]

Ubiquitin-binding domains

Table of characterized Ubiquitin-binding domains[85]
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

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.[85][86]

Disease associations


The ubiquitin pathway has been implicated in the pathogenesis of a wide range of diseases and disorders including:[87]


Ubiquitin is implicated in neurodegenerative diseases associated with proteostasis dysfunction, including Alzheimer's disease, motor neurone disease,[88] Huntington's disease and Parkinson's disease.[87] Transcript variants encoding different isoforms of ubiquilin-1 are found in lesions associated with Alzheimer's and Parkinson's disease.[89] Higher levels of ubiquilin in the brain have been shown to decrease malformation of amyloid precursor protein (APP), which plays a key role in triggering Alzheimer's disease.[90] Conversely, lower levels of ubiquilin-1 in the brain have been associated with increased malformation of APP.[90] A frameshift mutation in ubiquitin B can result in a truncated peptide missing the C-terminal glycine. This abnormal peptide, known as UBB+1, has been shown to accumulate selectively in Alzheimer's disease and other tauopathies.

Infection and immunity

Ubiquitin and ubiquitin-like molecules extensively regulate immune signal transduction pathways at virtually all stages, including steady-state repression, activation during infection, and attenuation upon clearance. Without this regulation, immune activation against pathogens may be defective, resulting in chronic disease or death. Alternatively, the immune system may become hyperactivated and organs and tissues may be subjected to autoimmune damage.

On the other hand, viruses must block or redirect host cell processes including immunity to effectively replicate, yet many viruses relevant to disease have informationally limited genomes. Because of its very large number of roles in the cell, manipulating the ubiquitin system represents an efficient way for such viruses to block, subvert or redirect critical host cell processes to support their own replication.[91]

The retinoic acid-inducible gene I (RIG-I) protein is a primary immune system sensor for viral and other invasive RNA in human cells.[92] The RIG-I-like receptor (RLR) immune signaling pathway is one of the most extensively studied in terms of the role of ubiquitin in immune regulation.[93]

Genetic Disorders

  • Angelman syndrome is caused by a disruption of UBE3A, which encodes a ubiquitin ligase (E3) enzyme termed E6-AP.
  • Von Hippel-Lindau syndrome involves disruption of a ubiquitin E3 ligase termed the VHL tumor suppressor, or VHL gene.
  • Fanconi anemia: Eight of the thirteen identified genes whose disruption can cause this disease encode proteins that form a large ubiquitin ligase (E3) complex.
  • 3-M syndrome is an autosomal-recessive growth retardation disorder associated with mutations of the Cullin7 E3 ubiquitin ligase.[94]

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:

Link to cancer

Post-translational modification of proteins is a generally used mechanism in eukaryotic cell signaling.[95] 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,[95] e.g. in endocytosis,[96] enzymatic activation[97] and DNA repair.[98] Moreover, since ubiquitination functions to tightly regulate the cellular level of cyclins, its misregulation is 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.[99][100][101] Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma.[102][103][104][105][106][107][108][109] 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.[110]

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.[102][110]

Breast cancer

The BRCA1 gene is another tumor suppressor gene in humans 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.[106][110]

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 control of cyclins or CDKs levels through ubiquitination and degradation. When cyclin E is partnered with CDK2 and gets phosphorylated, an SCF-associated F-box protein Fbw7 recognizes the complex and thus targets it for degradation. Mutations in Fbw7 have been found in more than 30% of human tumors, characterizing it as a tumor suppressor protein.[109]

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.[104] 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.[110] 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.[105][110]


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 cyclins E/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.[107][110]


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.[101][111] 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.[103][110]


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.[108]

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.[95] Moreover, ubiquitination can also act to turn on/off the kinase activity of a protein.[112] The critical role of phosphorylation is largely underscored in the activation and removal of autoinhibition in Cbl protein.[113] 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.[113] Phosphorylation of Y363 relieves the autoinhibition and enhances binding to E2.[113] 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.[114][115]

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.[116] 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 applications

Blocking of specific substrate recognition by the E3 ligases, e.g. Bortezomib.[111]


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.[101]

Similar proteins

Although ubiquitin is the most-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), Few ubiquitin-like protein (FUB1), MUB (membrane-anchored UBL),[117] ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe).[118][119] 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 they contain the same structural fold. This fold is called "ubiquitin 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.[73]

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.[120]

Prokaryotic origins

Ubiquitin is believed to have descended from bacterial proteins similar to ThiS (O32583)[121] or MoaD (P30748).[122] 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 molybdopterin 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.[123]

Archaea have a functionally closer homolog of the ubiquitin modification system, where "sampylation" with SAMPs (small archaeal modifier proteins) is performed. The sampylation system only uses E1 to guide proteins to the proteosome.[124] Proteoarchaeota, which are related to the ancestor of eukaryotes, possess all of the E1, E2, and E3 enzymes plus a regulated Rpn11 system. Unlike SAMP which are more similar to ThiS or MoaD, Proteoarchaeota ubiquitin are most similar to eukaryotic homologs.[125]

Prokaryotic ubiquitin-like protein (Pup) and ubiquitin bacterial (UBact)

Prokaryotic ubiquitin-like protein (Pup) is a functional analog of ubiquitin which has been found in the gram-positive bacterial phylum Actinobacteria. It serves the same function (targeting proteins for degradations), although the enzymology of ubiquitination and pupylation is different, and the two families share no homology. In contrast to the three-step reaction of ubiquitination, pupylation requires two steps, therefore only two enzymes are involved in pupylation.

In 2017, homologs of Pup were reported in five phyla of gram-negative bacteria, in seven candidate bacterial phyla and in one archaeon[126] The sequences of the Pup homologs are very different from the sequences of Pup in gram-positive bacteria and were termed Ubiquitin bacterial (UBact), although the distinction has yet not been proven to be phylogenetically supported by a separate evolutionary origin and is without experimental evidence.[126]

The finding of the Pup/UBact-proteasome system in both gram-positive and gram-negative bacteria suggests that either the Pup/UBact-proteasome system evolved in bacteria prior to the split into gram positive and negative clades over 3000 million years ago or,[127] that these systems were acquired by different bacterial lineages through horizontal gene transfer(s) from a third, yet unknown, organism. In support of the second possibility, two UBact loci were found in the genome of an uncultured anaerobic methanotrophic Archaeon (ANME-1;locus CBH38808.1 and locus CBH39258.1).

Human proteins containing ubiquitin domain

These include ubiquitin-like proteins.


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.[128]
  • 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.[129]
  • 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.[130]


  • Investigating the ubiquitin proteasome system was the focus of a Dementia Researcher Podcast.[131] The podcast was published on 16 August 2021, hosted by Professor Selina Wray from University College London.

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Ubiquitin-like protein Edit Wikipedia article

Ubiquitin family
1ubq 1ndd superposition.png
Superposition of the structures of ubiquitin (PDB: 1UBQ​, green) and NEDD8 (PDB: 1NDD​, magenta)

Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation.[1][2][3]


Ubiquitin itself was first discovered in the 1970s and originally named "ubiquitous immunopoietic polypeptide".[4] Subsequently, other proteins with sequence similarity to ubiquitin were occasionally reported in the literature, but the first shown to share the key feature of covalent protein modification was ISG15, discovered in 1987.[5] A succession of reports in the mid 1990s is recognized as a turning point in the field,[6] with the discovery of SUMO (small ubiquitin-like modifier, also known as Sentrin or SENP1) reported around the same time by a variety of investigators in 1996,[7] NEDD8 in 1997,[8] and Apg12 in 1998.[9] A systematic survey has since identified over 10,000 distinct genes for ubiquitin or ubiquitin-like proteins represented in eukaryotic genomes.[10]

Structure and classification

Members of the UBL family are small, non-enzymatic proteins that share a common structure exemplified by ubiquitin, which has 76 amino acid residues arranged into a "beta-grasp" protein fold consisting of a five-strand antiparallel beta sheet surrounding an alpha helix.[1][11][12] The beta-grasp fold is widely distributed in other proteins of both eukaryotic and prokaryotic origin.[13] Collectively, ubiquitin and ubiquitin-like proteins are sometimes referred to as "ubiquitons".[3]

UBLs can be divided into two categories depending on their ability to be covalently conjugated to other molecules. UBLs that are capable of conjugation (sometimes known as Type I) have a characteristic sequence motif consisting of one to two glycine residues at the C-terminus, through which covalent conjugation occurs. Typically, UBLs are expressed as inactive precursors and must be activated by proteolysis of the C-terminus to expose the active glycine.[1][12] Almost all such UBLs are ultimately linked to another protein, but there is at least one exception; ATG8 is linked to phosphatidylethanolamine.[1] UBLs that do not exhibit covalent conjugation (Type II) often occur as protein domains genetically fused to other domains in a single larger polypeptide chain, and may be proteolytically processed to release the UBL domain[1] or may function as protein-protein interaction domains.[11] UBL domains of larger proteins are sometimes known as UBX domains.[14]


Ubiquitin is, as its name suggests, ubiquitous in eukaryotes; it is traditionally considered to be absent in bacteria and archaea,[11] though a few examples have been described in archaea.[15] UBLs are also widely distributed in eukaryotes, but their distribution varies among lineages; for example, ISG15, involved in the regulation of the immune system, is not present in lower eukaryotes.[1] Other families exhibit diversification in some lineages; a single member of the SUMO family is found in the yeast genome, but there are at least four in vertebrate genomes, which show some functional redundancy,[1][2] and there are at least eight in the genome of the model plant Arabidopsis thaliana.[16]

In humans

The human genome encodes at least eight families of UBLs, not including ubiquitin itself, that are considered Type I UBLs and are known to covalently modify other proteins: SUMO, NEDD8, ATG8, ATG12, URM1, UFM1, FAT10, and ISG15.[1] One additional protein, known as FUBI, is encoded as a fusion protein in the FAU gene, and is proteolytically processed to generate a free glycine C-terminus, but has not been experimentally demonstrated to form covalent protein modifications.[1]

In plants

Plant genomes are known to encode at least seven families of UBLs in addition to ubiquitin: SUMO, RUB (the plant homolog of NEDD8), ATG8, ATG12, MUB, UFM1, and HUB1, as well as a number of Type II UBLs.[17] Some UBL families and their associated regulatory proteins in plants have undergone dramatic expansion, likely due to both whole genome duplication and other forms of gene duplication; the ubiquitin, SUMO, ATG8, and MUB families have been estimated to account for almost 90% of plants' UBL genes.[18] Proteins associated with ubiquitin and SUMO signaling are highly enriched in the genomes of embryophytes.[15]

In prokaryotes

Superposition of the structures of ubiquitin (PDB: 1UBQ​, green) and SAMP1 (PDB: 2L52​, orange)

In comparison to eukaryotes, prokaryotic proteins with relationships to UBLs are phylogenetically restricted.[19][20] Prokaryotic ubiquitin-like protein (Pup) occurs in some actinobacteria and has functions closely analogous to ubiquitin in labeling proteins for proteasomal degradation; however it is intrinsically disordered and its evolutionary relationship to UBLs is unclear.[19] A related protein UBact in some Gram-negative lineages has recently been described.[21] By contrast, the protein TtuB in bacteria of the genus Thermus does share the beta-grasp fold with eukaryotic UBLs; it is reported to have dual functions as both a sulfur carrier protein and a covalently conjugated protein modification.[19] In archaea, the small archaeal modifier proteins (SAMPs) share the beta-grasp fold and have been shown to play a ubiquitin-like role in protein degradation.[19][20] Recently, a seemingly complete set of genes corresponding to a eukaryote-like ubiquitin pathway was identified in an uncultured archaeon in 2011,[22][23][24] and at least three lineages of archaea - Euryarchaeota, Crenarchaeota, and Aigarchaeota - are believed to possess such systems.[15][25][26] In addition, some pathogenic bacteria have evolved proteins that mimic those in eukaryotic UBL pathways and interact with UBLs in the host cell, interfering with their signaling function.[27][28]


Crystal structure of the complex between the ubiquitin-like protein SUMO-1 (dark blue) and its activating enzyme (E1), a heterodimer between SAE1 and SAE2 (light blue, pink). The C-terminus of the SUMO protein is located near the ATP site (yellow). From PDB: 1Y8R​.

Regulation of UBLs that are capable of covalent conjugation in eukaryotes is elaborate but typically parallel for each member of the family, best characterized for ubiquitin itself. The process of ubiquitination is a tightly regulated three-step sequence: activation, performed by ubiquitin-activating enzymes (E1); conjugation, performed by ubiquitin-conjugating enzymes (E2); and ligation, performed by ubiquitin ligases (E3). The result of this process is the formation of a covalent bond between the C-terminus of ubiquitin and a residue (typically a lysine) on the target protein. Many UBL families have a similar three-step process catalyzed by a distinct set of enzymes specific to that family.[1][29][30] Deubiquitination or deconjugation - that is, removal of ubiquitin from a protein substrate - is performed by deubiquitinating enzymes (DUBs); UBLs can also be degraded through the action of ubiquitin-specific proteases (ULPs).[31] The range of UBLs on which these enzymes can act is variable and can be difficult to predict. Some UBLs, such as SUMO and NEDD8, have family-specific DUBs and ULPs.[32]

Ubiquitin is capable of forming polymeric chains, with additional ubiquitin molecules covalently attached to the first, which in turn is attached to its protein substrate. These chains may be linear or branched, and different regulatory signals may be sent by differences in the length and branching of the ubiquitin chain.[31] Although not all UBL families are known to form chains, SUMO, NEDD8, and URM1 chains have all been experimentally detected.[1] Additionally, ubiquitin can itself be modified by UBLs, known to occur with SUMO and NEDD8.[31][33] The best-characterized intersections between distinct UBL families involve ubiquitin and SUMO.[34][35]

Cellular functions

UBLs as a class are involved in a very large variety of cellular processes. Furthermore, individual UBL families vary in the scope of their activities and the diversity of the proteins to which they are conjugated.[1] The best known function of ubiquitin is identifying proteins to be degraded by the proteasome, but ubiquitination can play a role in other processes such as endocytosis and other forms of protein trafficking, transcription and transcription factor regulation, cell signaling, histone modification, and DNA repair.[11][12][36] Most other UBLs have similar roles in regulating cellular processes, usually with a more restricted known range than that of ubiquitin itself. SUMO proteins have the widest variety of cellular protein targets after ubiquitin[1] and are involved in processes including transcription, DNA repair, and the cellular stress response.[33] NEDD8 is best known for its role in regulating cullin proteins, which in turn regulate ubiquitin-mediated protein degradation,[2] though it likely also has other functions.[37] Two UBLs, ATG8 and ATG12, are involved in the process of autophagy;[38] both are unusual in that ATG12 has only two known protein substrates and ATG8 is conjugated not to a protein but to a phospholipid, phosphatidylethanolamine.[1]


Superposition of the structures of ubiquitin (PDB: 1UBQ​, green) and MoaD (PDB: 1FM0​, light gray)

The evolution of UBLs and their associated suites of regulatory proteins has been of interest since shortly after they were recognized as a family.[39] Phylogenetic studies of the beta-grasp protein fold superfamily suggest that eukaryotic UBLs are monophyletic, indicating a shared evolutionary origin.[13] UBL regulatory systems - including UBLs themselves and the cascade of enzymes that interact with them - are believed to share a common evolutionary origin with prokaryotic biosynthesis pathways for the cofactors thiamine and molybdopterin; the bacterial sulfur transfer proteins ThiS and MoaD from these pathways share the beta-grasp fold with UBLs, while sequence similarity and a common catalytic mechanism link pathway members ThiF and MoeB to ubiquitin-activating enzymes.[13][17][11] Interestingly, the eukaryotic protein URM1 functions as both a UBL and a sulfur-carrier protein, and has been described as a molecular fossil establishing this evolutionary link.[11][40]

Comparative genomics surveys of UBL families and related proteins suggest that UBL signaling was already well-developed in the last eukaryotic common ancestor and ultimately originates from ancestral archaea,[15] a theory supported by the observation that some archaeal genomes possess the necessary genes for a fully functioning ubiquitination pathway.[25][18] Two different diversification events within the UBL family have been identified in eukaryotic lineages, corresponding to the origin of multicellularity in both animal and plant lineages.[15]


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  9. ^ Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y (September 1998). "A protein conjugation system essential for autophagy". Nature. 395 (6700): 395–8. Bibcode:1998Natur.395..395M. doi:10.1038/26506. PMID 9759731. S2CID 204997310.
  10. ^ Zhou J, Xu Y, Lin S, Guo Y, Deng W, Zhang Y, Guo A, Xue Y (January 2018). "iUUCD 2.0: an update with rich annotations for ubiquitin and ubiquitin-like conjugations". Nucleic Acids Research. 46 (D1): D447–D453. doi:10.1093/nar/gkx1041. PMC 5753239. PMID 29106644.
  11. ^ a b c d e f Hochstrasser M (March 2009). "Origin and function of ubiquitin-like proteins". Nature. 458 (7237): 422–9. Bibcode:2009Natur.458..422H. doi:10.1038/nature07958. PMC 2819001. PMID 19325621.
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  13. ^ a b c Burroughs AM, Balaji S, Iyer LM, Aravind L (July 2007). "Small but versatile: the extraordinary functional and structural diversity of the beta-grasp fold". Biology Direct. 2 (1): 18. doi:10.1186/1745-6150-2-18. PMC 1949818. PMID 17605815.
  14. ^ Buchberger A, Howard MJ, Proctor M, Bycroft M (March 2001). "The UBX domain: a widespread ubiquitin-like module". Journal of Molecular Biology. 307 (1): 17–24. doi:10.1006/jmbi.2000.4462. PMID 11243799.
  15. ^ a b c d e Grau-Bové X, Sebé-Pedrós A, Ruiz-Trillo I (March 2015). "The eukaryotic ancestor had a complex ubiquitin signaling system of archaeal origin". Molecular Biology and Evolution. 32 (3): 726–39. doi:10.1093/molbev/msu334. PMC 4327156. PMID 25525215.
  16. ^ Miura K, Hasegawa PM (April 2010). "Sumoylation and other ubiquitin-like post-translational modifications in plants". Trends in Cell Biology. 20 (4): 223–32. doi:10.1016/j.tcb.2010.01.007. PMID 20189809.
  17. ^ a b Vierstra RD (September 2012). "The expanding universe of ubiquitin and ubiquitin-like modifiers". Plant Physiology. 160 (1): 2–14. doi:10.1104/pp.112.200667. PMC 3440198. PMID 22693286.
  18. ^ a b Hua Z, Doroodian P, Vu W (July 2018). "Contrasting duplication patterns reflect functional diversities of ubiquitin and ubiquitin-like protein modifiers in plants". The Plant Journal. 95 (2): 296–311. doi:10.1111/tpj.13951. PMID 29738099.
  19. ^ a b c d Maupin-Furlow JA (2014). "Prokaryotic ubiquitin-like protein modification". Annual Review of Microbiology. 68: 155–75. doi:10.1146/annurev-micro-091313-103447. PMC 4757901. PMID 24995873.
  20. ^ a b Ganguli, S; Ratna Prabha, C (2017). "Pups, SAMPs, and Prokaryotic Proteasomes". In Chakraborti, S; Dhalla, N (eds.). Proteases in physiology and pathology. Springer. ISBN 978-981-10-2512-9.
  21. ^ Lehmann G, Udasin RG, Livneh I, Ciechanover A (February 2017). "Identification of UBact, a ubiquitin-like protein, along with other homologous components of a conjugation system and the proteasome in different gram-negative bacteria". Biochemical and Biophysical Research Communications. 483 (3): 946–950. doi:10.1016/j.bbrc.2017.01.037. PMID 28087277.
  22. ^ Nunoura T, Takaki Y, Kakuta J, Nishi S, Sugahara J, Kazama H, Chee GJ, Hattori M, Kanai A, Atomi H, Takai K, Takami H (April 2011). "Insights into the evolution of Archaea and eukaryotic protein modifier systems revealed by the genome of a novel archaeal group". Nucleic Acids Research. 39 (8): 3204–23. doi:10.1093/nar/gkq1228. PMC 3082918. PMID 21169198.
  23. ^ Hennell James R, Caceres EF, Escasinas A, Alhasan H, Howard JA, Deery MJ, Ettema TJ, Robinson NP (October 2017). "Functional reconstruction of a eukaryotic-like E1/E2/(RING) E3 ubiquitylation cascade from an uncultured archaeon". Nature Communications. 8 (1): 1120. Bibcode:2017NatCo...8.1120H. doi:10.1038/s41467-017-01162-7. PMC 5654768. PMID 29066714.
  24. ^ Fuchs AC, Maldoner L, Wojtynek M, Hartmann MD, Martin J (July 2018). "Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system". Nature Communications. 9 (1): 2696. Bibcode:2018NatCo...9.2696F. doi:10.1038/s41467-018-05198-1. PMC 6043591. PMID 30002364.
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  26. ^ Hua ZS, Qu YN, Zhu Q, Zhou EM, Qi YL, Yin YR, Rao YZ, Tian Y, Li YX, Liu L, Castelle CJ, Hedlund BP, Shu WS, Knight R, Li WJ (July 2018). "Genomic inference of the metabolism and evolution of the archaeal phylum Aigarchaeota". Nature Communications. 9 (1): 2832. Bibcode:2018NatCo...9.2832H. doi:10.1038/s41467-018-05284-4. PMC 6053391. PMID 30026532.
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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

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000626

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.

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 expressed as three different precursors: a polymeric head-to-tail concatemer of identical units (polyubiquitin), and two N-terminal ubiquitin moieties, UbL40 and UbS27, that are fused to the ribosomal polypeptides L40 and S27, respectively. Specific endopeptidases cleave these precursor molecules [ PUBMED:15571815 ] to release ubiquitin moieties that are identical in sequence and contribute to the ubiquitin pool [ PUBMED:16185873 ]. Some organisms express additional ubiquitin fusion proteins [ PUBMED:12729753 ]. Furthermore, there are several ubiquitin-like proteins derived from ubiquitin [ PUBMED:12826404 ].

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 ].

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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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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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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.

Representative proteomes UniProt
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Representative proteomes UniProt

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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.

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

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...


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
Sequence Ontology: SO:0000417
Author: Finn RD , Griffiths-Jones SR
Number in seed: 60
Number in full: 53635
Average length of the domain: 70.50 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 22.83 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
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: 26
Download: download the raw HMM for this family

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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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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The tree shows the occurrence of this domain across different species. More...


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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 1954 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A096MJP9 View 3D Structure Click here
A0A0A6YW67 View 3D Structure Click here
A0A0G2K6W0 View 3D Structure Click here
A0A0G2K7M2 View 3D Structure Click here
A0A0G2K9U8 View 3D Structure Click here
A0A0H2UKX4 View 3D Structure Click here
A0A0N4SUD2 View 3D Structure Click here
A0A0N7KFQ6 View 3D Structure Click here
A0A0P0V079 View 3D Structure Click here
A0A0P0VC20 View 3D Structure Click here
A0A0P0VF30 View 3D Structure Click here
A0A0P0VVN4 View 3D Structure Click here
A0A0P0X005 View 3D Structure Click here
A0A0P0X0E0 View 3D Structure Click here
A0A0P0X6D6 View 3D Structure Click here
A0A0P0X6U8 View 3D Structure Click here
A0A0P0XE68 View 3D Structure Click here
A0A0P0XW22 View 3D Structure Click here
A0A0P0XYN0 View 3D Structure Click here
A0A0P0Y727 View 3D Structure Click here
A0A0R0GC27 View 3D Structure Click here
A0A0R0ICM5 View 3D Structure Click here
A0A0R0IPI1 View 3D Structure Click here
A0A0R0IY29 View 3D Structure Click here
A0A0R0J999 View 3D Structure Click here
A0A0R4IIH0 View 3D Structure Click here
A0A143ZYV5 View 3D Structure Click here
A0A1B0GRQ3 View 3D Structure Click here
A0A1D6DUU8 View 3D Structure Click here
A0A1D6DZ72 View 3D Structure Click here
A0A1D6EPM8 View 3D Structure Click here
A0A1D6ES07 View 3D Structure Click here
A0A1D6HLZ4 View 3D Structure Click here
A0A1D6I428 View 3D Structure Click here
A0A1D6I4G6 View 3D Structure Click here
A0A1D6I6V9 View 3D Structure Click here
A0A1D6JMS0 View 3D Structure Click here
A0A1D6K7R6 View 3D Structure Click here
A0A1D6KL36 View 3D Structure Click here
A0A1D6L8S4 View 3D Structure Click here