Ubiquitin - Related Links
Open Access Articles- Top Results for Ubiquitin
Journal of Carcinogenesis & MutagenesisPristimerin Induces Apoptosis in Prostate Cancer Cells by Downregulating Bcl-2 through ROS-dependent Ubiquitin-proteasomal Degradation Pathway
Biology and MedicinePhylogeny reconstrution of ubiquitin conjugating (E2) enzymes
Clinical & Experimental PharmacologyTargeting Breast Cancer Associated Gene 2 (bca2), a Novel Ubiquitin e3 Ligase for Breast Cancer Treatment
Clinical Pharmacology & BiopharmaceuticsShould Deubiquitinating Enzymes be Targeted for Therapy?
Biochemistry & Analytical BiochemistryOncogenic Signaling by Leukemia-Associated Mutant Cbl Proteins
A diagram of ubiquitin. The seven lysine sidechains are shown in yellow/orange.
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 by Goldstein and further characterized throughout the 1970s and 1980s. There are four genes in the human genome that produce ubiquitin: UBB, UBC, UBA52 and RPS27A.
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. 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 or to the amino group of the protein's N-terminus via a peptide bond.
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 from the ubiquitin molecule. These 'linking' lysines are represented by a "K" (which is the one-letter amino acid notation of lysine) 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 (e.g. K48, K29, K63,...) on the target protein. Poly-ubiquitination occurs when the C-terminus of another ubiquitin, will be linked again to a lysine residue (for example again K48 or K29) on the previously added ubiquitin molecule, 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 with the proteasome (referred to as the "molecular kiss of death"), while other polyubiquitinations (e.g. on K63, K11, K6) and monoubiquitinations may regulate processes such as endocytic trafficking, inflammation, translation and DNA repair.
Lysine 48-linked chains have been much-studied. They are the forms of chains that signal proteins to the proteasome, which destroys and recycles proteins. This discovery won the Nobel Prize for chemistry in 2004.
- 1 Identification
- 2 The protein
- 3 Genes
- 4 Origins
- 5 Ubiquitination
- 6 Variety of ubiquitin modifications
- 7 Functions of ubiquitin modification
- 8 Deubiquitination
- 9 Ubiquitin-binding domains
- 10 Disease associations
- 11 Ubiquitin-like modifiers
- 12 Prokaryotic ubiquitin-like protein (Pup)
- 13 Human proteins containing ubiquitin domain
- 14 Related proteins
- 15 Prediction of ubiquitination
- 16 See also
- 17 References
- 18 External links
Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975 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.
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. 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.
|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
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.
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.
No ubiquitin and ubiquitination machinery are known to exist in prokaryotes. However, ubiquitin is believed to have descended from prokaryotic proteins similar to ThiS or MoaD. 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.
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. Trypsin cleavage of a ubiquitin-conjugated substrate leaves a di-glycine "remnant" that is used to identify the site of ubiquitination. Cases are known in which the amine group of a protein's N-terminus is used for ubiquitination, rather than a lysine residue. In a few rare cases nonlysine residues have been identified as ubiquitination targets, such as cysteine, threonine and serine. 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.
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:
- 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. The human genome contains two genes that produce enzymes capable of activating ubiquitin: UBA1 and UBA6.
- 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.
- 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. 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.
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. Other ubiquitin-like proteins (UBLs) are also modified via the E1–E2–E3 cascade, although variations in these systems do exist.
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. 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).
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. Monoubiquitination affects cellular processes such as membrane trafficking, endocytosis and viral budding.
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. 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.
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. 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. Although the majority of protein substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome. 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.
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. 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.
Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains. There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and N-terminal chains can induce proteasomal degradation.
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 29-, 33-, 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.
Functions of ubiquitin modification
The ubiquitination system functions in a wide variety of cellular processes, including:
- Antigen processing
- 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
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.
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.
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. 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.
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.
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.
|Domain|| Number of Proteins
| Ubiquitin Binding
|CUE|| S. cerevisiae 7
H. sapiens 21
|GATII|| S. cerevisiae 2
H. sapiens 14
|GLUE|| S. cerevisiae ?
H. sapiens ?
|NZF|| S. cerevisiae 1
H. sapiens 25
|PAZ|| S. cerevisiae 5
H. sapiens 16
|UBA|| S. cerevisiae 10
H. sapiens 98
|UEV|| S. cerevisiae 2
H. sapiens ?
|UIM|| S. cerevisiae 8
H. sapiens 71
|VHS|| S. cerevisiae 4
H. sapiens 28
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.
The ubiquitin pathway has been implicated in the pathogenesis of several diseases and genetic disorders:
- Neurodegenerative disorders: Transcript variants encoding different isoforms of ubiquilin-1 are found in lesions associated with Alzheimer's and Parkinson's disease. 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. Conversely, lower levels of ubiquilin-1 in the brain have been associated with increased malformation of APP. 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.
- 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.
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:
- Neurofibrillary tangles in Alzheimer's disease
- Lewy body in Parkinson's disease
- Pick bodies in Pick's disease
- Inclusions in motor neuron disease and Huntington's Disease
- Mallory bodies in alcoholic liver disease
- Rosenthal fibers in astrocytes
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), Fau ubiquitin-like protein (FUB1), MUB (membrane-anchored UBL), ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe). Whilst these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but they 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.
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.
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; C1orf131; 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;
Prediction of ubiquitination
Currently available prediction programs are:
- UbiPred is a SVM-based prediction server using 31 physicochemical properties for predicting ubiquitination sites.
- 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.
- 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, usess the same dataset as UbPred.
- SUMO protein
- SUMO enzymes
- Ubiquitin ligase
- Prokaryotic ubiquitin-like protein
- JUNQ and IPOD
- Deubiquitinating enzyme
- Goldstein G, Scheid M, Hammerling U, Schlesinger DH, Niall HD, Boyse EA (January 1975). "Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells". Proc. Natl. Acad. Sci. U.S.A. 72 (1): 11–5. PMC 432229. PMID 1078892. doi:10.1073/pnas.72.1.11.
- Wilkinson KD (October 2005). "The discovery of ubiquitin-dependent proteolysis". Proc. Natl. Acad. Sci. U.S.A. 102 (43): 15280–2. PMC 1266097. PMID 16230621. doi:10.1073/pnas.0504842102.
- Kimura Y, Tanaka K (2010). "Regulatory mechanisms involved in the control of ubiquitin homeostasis". J Biochem 147 (6): 793–8. PMID 20418328. doi:10.1093/jb/mvq044.
- Glickman MH, Ciechanover A (April 2002). "The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction". Physiol. Rev. 82 (2): 373–428. PMID 11917093. doi:10.1152/physrev.00027.2001.
- Mukhopadhyay D, Riezman H (January 2007). "Proteasome-independent functions of ubiquitin in endocytosis and signaling". Science 315 (5809): 201–5. PMID 17218518. doi:10.1126/science.1127085.
- Schnell JD, Hicke L (September 2003). "Non-traditional functions of ubiquitin and ubiquitin-binding proteins". J. Biol. Chem. 278 (38): 35857–60. PMID 12860974. doi:10.1074/jbc.R300018200.
- Pickart CM, Eddins MJ (November 2004). "Ubiquitin: structures, functions, mechanisms". Biochim. Biophys. Acta 1695 (1–3): 55–72. PMID 15571809. doi:10.1016/j.bbamcr.2004.09.019.
- Komander D, Rape M (2012). "The ubiquitin code". Annu. Rev. Biochem. 81: 203–29. PMID 22524316. doi:10.1146/annurev-biochem-060310-170328.
- Miranda M, Sorkin A (June 2007). "Regulation of receptors and transporters by ubiquitination: new insights into surprisingly similar mechanisms". Mol. Interv. 7 (3): 157–67. PMID 17609522. doi:10.1124/mi.7.3.7.
- "The Nobel Prize in Chemistry 2004". Nobelprize.org. Retrieved 2010-10-16.
- "The Nobel Prize in Chemistry 2004: Popular Information". Nobelprize.org. Retrieved 2013-12-14.
- Ciechanover A, Hod Y, Hershko A (August 2012). "A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. 1978". Biochem. Biophys. Res. Commun. 425 (3): 565–70. PMID 22925675. doi:10.1016/j.bbrc.2012.08.025.
- Wang C, Xi J, Begley TP, Nicholson LK (January 2001). "Solution structure of ThiS and implications for the evolutionary roots of ubiquitin". Nat. Struct. Biol. 8 (1): 47–51. PMID 11135670. doi:10.1038/83041.
- Lake MW, Wuebbens MM, Rajagopalan KV, Schindelin H (November 2001). "Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex". Nature 414 (6861): 325–9. PMID 11713534. doi:10.1038/35104586.
- Hochstrasser M (March 2009). "Origin and function of ubiquitin-like proteins". Nature 458 (7237): 422–9. PMC 2819001. PMID 19325621. doi:10.1038/nature07958.
- Pickart CM (2001). "Mechanisms underlying ubiquitination". Annu. Rev. Biochem. 70: 503–33. PMID 11395416. doi:10.1146/annurev.biochem.70.1.503.
- Marotti LM, Newitt R, Wang Y, Aebersold R, Dohlman HG (2002). "Direct identification of a G protein ubiquitination site by mass spectrometry". Biochemistry. 41 (16): 5067–74. PMID 11955054. doi:10.1021/bi015940q.
- Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J, Finley D, Gygi SP (August 2003). "A proteomics approach to understanding protein ubiquitination". Nat. Biotechnol. 21 (8): 921–6. PMID 12872131. doi:10.1038/nbt849.
- Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M (October 2003). "Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation". Cell 115 (1): 71–82. PMID 14532004. doi:10.1016/S0092-8674(03)00755-4.
- Scaglione KM, Basrur V, Ashraf NS et al. (June 2013). "The Ubiquitin-conjugating Enzyme (E2) Ube2w Ubiquitinates the N Terminus of Substrates". J. Biol. Chem. 288 (26): 18784–8. PMC 3696654. PMID 23696636. doi:10.1074/jbc.C113.477596.
- Breitschopf K, Bengal E, Ziv T, Admon A, Ciechanover A (October 1998). "A novel site for ubiquitination: the N-terminal residue, and not internal lysines of MyoD, is essential for conjugation and degradation of the protein". EMBO J. 17 (20): 5964–73. PMC 1170923. PMID 9774340. doi:10.1093/emboj/17.20.5964.
- Wang X, Herr RA, Chua WJ, Lybarger L, Wiertz EJ, Hansen TH (May 2007). "Ubiquitination of serine, threonine, or lysine residues on the cytoplasmic tail can induce ERAD of MHC-I by viral E3 ligase mK3". J. Cell Biol. 177 (4): 613–24. PMC 2064207. PMID 17502423. doi:10.1083/jcb.200611063.
- Cadwell K, Coscoy L (July 2005). "Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase". Science 309 (5731): 127–30. PMID 15994556. doi:10.1126/science.1110340.
- Dikic I, Robertson M (2012). "Ubiquitin ligases and beyond". BMC Biol. 10: 22. PMC 3305657. PMID 22420755. doi:10.1186/1741-7007-10-22.
- Schulman BA, Harper JW (May 2009). "Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways". Nat. Rev. Mol. Cell Biol. 10 (5): 319–31. PMC 2712597. PMID 19352404. doi:10.1038/nrm2673.
- Groettrup M, Pelzer C, Schmidtke G, Hofmann K (May 2008). "Activating the ubiquitin family: UBA6 challenges the field". Trends Biochem. Sci. 33 (5): 230–7. PMID 18353650. doi:10.1016/j.tibs.2008.01.005.
- van Wijk SJ, Timmers HT (April 2010). "The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins". FASEB J. 24 (4): 981–93. PMID 19940261. doi:10.1096/fj.09-136259.
- Metzger MB, Hristova VA, Weissman AM (February 2012). "HECT and RING finger families of E3 ubiquitin ligases at a glance". J. Cell. Sci. 125 (Pt 3): 531–7. PMC 3381717. PMID 22389392. doi:10.1242/jcs.091777.
- Skaar JR, Pagano M (December 2009). "Control of cell growth by the SCF and APC/C ubiquitin ligases". Curr. Opin. Cell Biol. 21 (6): 816–24. PMC 2805079. PMID 19775879. doi:10.1016/j.ceb.2009.08.004.
- Kerscher O, Felberbaum R, Hochstrasser M (2006). "Modification of proteins by ubiquitin and ubiquitin-like proteins". Annu. Rev. Cell Dev. Biol. 22: 159–80. PMID 16753028. doi:10.1146/annurev.cellbio.22.010605.093503.
- Komander D (October 2009). "The emerging complexity of protein ubiquitination". Biochem. Soc. Trans. 37 (Pt 5): 937–53. PMID 19754430. doi:10.1042/BST0370937.
- Ikeda F, Dikic I (June 2008). "Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series". EMBO Rep. 9 (6): 536–42. PMC 2427391. PMID 18516089. doi:10.1038/embor.2008.93.
- Xu P, Peng J (May 2008). "Characterization of polyubiquitin chain structure by middle-down mass spectrometry". Anal. Chem. 80 (9): 3438–44. PMC 2663523. PMID 18351785. doi:10.1021/ac800016w.
- Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, Sano S, Tokunaga F, Tanaka K, Iwai K (October 2006). "A ubiquitin ligase complex assembles linear polyubiquitin chains". EMBO J. 25 (20): 4877–87. PMC 1618115. PMID 17006537. doi:10.1038/sj.emboj.7601360.
- Hicke L (March 2001). "Protein regulation by monoubiquitin". Nat. Rev. Mol. Cell Biol. 2 (3): 195–201. PMID 11265249. doi:10.1038/35056583.
- 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. PMID 16738015. doi:10.1681/ASN.2006010083.
- Kravtsova-Ivantsiv Y, Ciechanover A (February 2012). "Non-canonical ubiquitin-based signals for proteasomal degradation". J. Cell. Sci. 125 (Pt 3): 539–48. PMID 22389393. doi:10.1242/jcs.093567.
- Nathan JA, Kim HT, Ting L, Gygi SP, Goldberg AL (February 2013). "Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes?". EMBO J. 32 (4): 552–65. PMC 3579138. PMID 23314748. doi:10.1038/emboj.2012.354.
- 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. PMID 12551915. doi:10.1074/jbc.M210843200.
- 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. PMC 2867854. PMID 20385835. doi:10.1073/pnas.0908764107.
- 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. PMID 17426036. doi:10.1074/jbc.M609659200.
- Michel MA, Elliot PR, Swatek KN et al. "Assembly and Specific Recognition of K29- and K33-Linked Polyubiquitin". Mol Cell. PMID 25752577. doi:10.1016/j.molcel.2015.01.042.
- "Ubiquitin Proteasome Pathway Overview". Archived from the original on 2008-03-30. Retrieved 2008-04-30.
- Shaheen M, Shanmugam I, Hromas R (2010). "The Role of PCNA Posttranslational Modifications in Translesion Synthesis". J Nucleic Acids 2010: 1. PMC 2935186. PMID 20847899. doi:10.4061/2010/761217.
- Jackson SP, Durocher D (March 2013). "Regulation of DNA damage responses by ubiquitin and SUMO". Mol. Cell 49 (5): 795–807. PMID 23416108. doi:10.1016/j.molcel.2013.01.017.
- 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. PMC 3390666. PMID 22589545. doi:10.1074/jbc.M112.359653.
- 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. PMC 2168918. PMID 17709392. doi:10.1128/MCB.00579-07.
- Kim H, Chen J, Yu X (May 2007). "Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response". Science 316 (5828): 1202–5. PMID 17525342. doi:10.1126/science.1139621.
- Hofmann K (April 2009). "Ubiquitin-binding domains and their role in the DNA damage response". DNA Repair (Amst.) 8 (4): 544–56. PMID 19213613. doi:10.1016/j.dnarep.2009.01.003.
- Hammond-Martel I, Yu H, Affar el B (February 2012). "Roles of ubiquitin signaling in transcription regulation". Cell. Signal. 24 (2): 410–21. PMID 22033037. doi:10.1016/j.cellsig.2011.10.009.
- Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009). "Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes". Annu. Rev. Biochem. 78: 363–97. PMC 2734102. PMID 19489724. doi:10.1146/annurev.biochem.78.082307.091526.
- Nijman SM, Luna-Vargas MP, Velds A et al. (December 2005). "A genomic and functional inventory of deubiquitinating enzymes". Cell 123 (5): 773–86. PMID 16325574. doi:10.1016/j.cell.2005.11.007.
- Hicke L, Schubert HL, Hill CP (August 2005). "Ubiquitin-binding domains". Nat. Rev. Mol. Cell Biol. 6 (8): 610–21. PMID 16064137. doi:10.1038/nrm1701.
- "UBQLN1 ubiquilin 1 [ Homo sapiens ]". Gene. National Center for Biotechnology Information. Retrieved 9 May 2012.
- Stieren ES, El Ayadi A, Xiao Y, Siller E, Landsverk ML, Oberhauser AF, Barral JM, Boehning D (August 2011). "Ubiquilin-1 Is a Molecular Chaperone for the Amyloid Precursor Protein". J Biol Chem 286 (41): 35689–98. PMC 3195644. PMID 21852239. doi:10.1074/jbc.M111.243147. Lay summary – Science Daily.
- Huber C, Dias-Santagata D, Glaser A, O'Sullivan J, Brauner R, Wu K, Xu X, Pearce K, Wang R, Uzielli ML, Dagoneau N, Chemaitilly W, Superti-Furga A, Dos Santos H, Mégarbané A, Morin G, Gillessen-Kaesbach G, Hennekam R, Van der Burgt I, Black GC, Clayton PE, Read A, Le Merrer M, Scambler PJ, Munnich A, Pan ZQ, Winter R, Cormier-Daire V (October 2005). "Identification of mutations in CUL7 in 3-M syndrome". Nat. Genet. 37 (10): 1119–24. PMID 16142236. doi:10.1038/ng1628.
- Downes BP, Saracco SA, Lee SS, Crowell DN, Vierstra RD (September 2006). "MUBs, a family of ubiquitin-fold proteins that are plasma membrane-anchored by prenylation". J. Biol. Chem. 281 (37): 27145–57. PMID 16831869. doi:10.1074/jbc.M602283200.
- Welchman RL, Gordon C, Mayer RJ (2005). "Ubiquitin and ubiquitin-like proteins as multifunctional signals". Nat Rev Mol Cell Biol 6 (8): 599–609. PMID 16064136. doi:10.1038/nrm1700.
- Grabbe C, Dikic I (2009). "Functional roles of ubiquitin-like domain (ULD) and ubiquitin-binding domain (UBD) containing proteins". Chem Rev 109 (4): 1481–94. PMID 19253967. doi:10.1021/cr800413p.
- Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G (August 2000). "Ubiquitinated sperm mitochondria, selective proteolysis, and the regulation of mitochondrial inheritance in mammalian embryos". Biol. Reprod. 63 (2): 582–90. PMID 10906068. doi:10.1095/biolreprod63.2.582.
- Tung CW, Ho SY (2008). "Computational identification of ubiquitylation sites from protein sequences". BMC Bioinformatics 9: 310. PMC 2488362. PMID 18625080. doi:10.1186/1471-2105-9-310.
- Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A, Heyen JW, Goebl MG, Iakoucheva LM (February 2010). "Identification, analysis, and prediction of protein ubiquitination sites". Proteins 78 (2): 365–80. PMC 3006176. PMID 19722269. doi:10.1002/prot.22555.
- Chen Z, Chen YZ, Wang XF, Wang C, Yan RX, Zhang Z (2011). Fraternali, Franca, ed. "Prediction of ubiquitination sites by using the composition of k-spaced amino acid pairs". PLoS ONE 6 (7): e22930. PMC 3146527. PMID 21829559. doi:10.1371/journal.pone.0022930.
- GeneReviews/NCBI/NIH/UW entry on Angelman syndrome
- OMIM entries on Angelman syndrome
- UniProt entry for ubiquitin
- "7.340 Ubiquitination: The Proteasome and Human Disease". MIT OpenCourseWare. 2004. Notes from MIT course.
- Ubiquitin at the US National Library of Medicine Medical Subject Headings (MeSH)
Lua error in Module:Authority_control at line 346: attempt to index field 'wikibase' (a nil value).