Deubiquitinating enzyme
Encyclopedia
Deubiquitinating enzymes (DUBs) are a large group of protease
s (more than 60 known) that regulate ubiquitin
-dependent metabolic pathways by cleaving ubiquitin-protein bonds. DUBs are also commonly referred to as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolyases, ubiquitin isopeptidases, or DUbs. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Potentially, DUBs may act as negative and positive regulators of the ubiquitin system. In addition to ubiquitin recycling, they are involved in processing of ubiquitin precursors, in proofreading of protein ubiquitination and in disassembly of inhibitory ubiquitin chains.
They may be associated with disease.
s and metalloproteases.
However, there is also a little known putative group of DUBs called the permutated papain fold peptidases of dsDNA viruses and eukaryote (PPPDEs) superfamily, which, if shown to be bona fide DUBs, would be the fifth in the cysteine protease class.
despite of the fact that the glycine at position 76 is mutated.
surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain. The DUSP domain displays a tripod-like AB3 fold
with a three-helix
bundle and a three-stranded anti-parallel beta-sheet resembling the legs and seat of the tripod. Conserved
residues
are predominantly involved in hydrophobic packing interactions within the three alpha-helices
. The most conserved
DUSP residues, forming the PGPI motif, are flanked by two long loops that vary both in length and sequence
. The PGPI motif packs against the three-helix bundle and is highly ordered. The function of the DUSP domain is unknown but it may play a role in protein/protein interaction or substrate recognition.
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s (more than 60 known) that regulate ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
-dependent metabolic pathways by cleaving ubiquitin-protein bonds. DUBs are also commonly referred to as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolyases, ubiquitin isopeptidases, or DUbs. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Potentially, DUBs may act as negative and positive regulators of the ubiquitin system. In addition to ubiquitin recycling, they are involved in processing of ubiquitin precursors, in proofreading of protein ubiquitination and in disassembly of inhibitory ubiquitin chains.
They may be associated with disease.
Classes
DUBs can be classified into two main classes: cysteine proteaseCysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
s and metalloproteases.
Cysteine proteases
There are four main superfamilies of cysteine protease DUBs:- the ubiquitin-specific processing protease (USP/UBP) superfamily; (USP1USP1Ubiquitin carboxyl-terminal hydrolase 1 is an enzyme that in humans is encoded by the USP1 gene.-Further reading:...
, USP2USP2Ubiquitin carboxyl-terminal hydrolase 2 is an enzyme that in humans is encoded by the USP2 gene.-Further reading:...
, USP3, USP4USP4Ubiquitin carboxyl-terminal hydrolase 4 is an enzyme that in humans is encoded by the USP4 gene. This protein is a member of cysteine peptidase family C19.-Interactions:USP4 has been shown to interact with Retinoblastoma protein.-Further reading:...
, USP5USP5Ubiquitin carboxyl-terminal hydrolase 5 is an enzyme that in humans is encoded by the USP5 gene.-Further reading:...
, USP6USP6Ubiquitin carboxyl-terminal hydrolase 6 is an enzyme that in humans is encoded by the USP6 gene.Aneurysmal bone cyst can be associated with a TRE17/USP6 translocation.-Further reading:...
, USP7USP7Ubiquitin-specific-processing protease 7 also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease is an enzyme that in humans is encoded by the USP7 gene....
, USP8USP8Ubiquitin carboxyl-terminal hydrolase 8 is an enzyme that in humans is encoded by the USP8 gene.-Interactions:USP8 has been shown to interact with RNF41 and STAM2.-Further reading:...
, USP9XUSP9XProbable ubiquitin carboxyl-terminal hydrolase FAF-X is an enzyme that in humans is encoded by the USP9X gene.-Interactions:USP9X has been shown to interact with Beta-catenin, MARK4, NUAK1 and MLLT4.-Further reading:...
, USP9YUSP9YUbiquitin specific peptidase 9, Y-linked , also known as USP9Y, is an enzyme which in humans is encoded by the USP9Y gene. It is required for sperm production...
, USP10USP10Ubiquitin specific peptidase 10, also known as USP10, is an enzyme which in humans is encoded by the USP10 gene.- Function :Ubiquitin is a highly conserved protein that is covalently linked to other proteins to regulate their function and degradation. This gene encodes a member of the...
, USP11USP11Ubiquitin carboxyl-terminal hydrolase 11 is an enzyme that in humans is encoded by the USP11 gene.-Further reading:...
, USP12, USP13USP13Ubiquitin carboxyl-terminal hydrolase 13 is an enzyme that in humans is encoded by the USP13 gene.-Further reading:...
, USP14USP14Ubiquitin carboxyl-terminal hydrolase 14 is an enzyme that in humans is encoded by the USP14 gene.This gene encodes a member of the ubiquitin-specific processing family of proteases that is a deubiquitinating enzyme with His and Cys domains...
, USP15USP15Ubiquitin carboxyl-terminal hydrolase 15 is an enzyme that in humans is encoded by the USP15 gene.-Further reading:...
, USP16USP16Ubiquitin carboxyl-terminal hydrolase 16 is an enzyme that in humans is encoded by the USP16 gene.-Further reading:...
, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18USP18Ubiquitin specific peptidase 18 , also known as UBP43, is a gene.-Further reading:...
, USP19, USP20USP20Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.-Further reading:...
, USP21, USP22, USP23, USP24USP24Ubiquitin carboxyl-terminal hydrolase 24 is an enzyme that in humans is encoded by the USP24 gene.-Further reading:...
, USP25, USP26USP26USP26 is a peptidase enzyme.Recent research has suggested that defects in USP26 may be involved in some cases of male infertility....
, USP27X, USP28, USP29, USP30, USP31, USP32, USP33USP33Ubiquitin carboxyl-terminal hydrolase 33 is an enzyme that in humans is encoded by the USP33 gene.-Interactions:USP33 has been shown to interact with DIO2, SELENBP1 and Von Hippel-Lindau tumor suppressor.-Further reading:...
, USP34USP34Ubiquitin carboxyl-terminal hydrolase 34 is an enzyme that in humans is encoded by the USP34 gene.-Further reading:...
, USP35, USP36USP36Ubiquitin carboxyl-terminal hydrolase 36 is an enzyme that in humans is encoded by the USP36 gene.-Further reading:...
, USP37USP37Ubiquitin carboxyl-terminal hydrolase 37 is an enzyme that in humans is encoded by the USP37 gene.-Further reading:...
, USP38, USP39USP39U4/U6.U5 tri-snRNP-associated protein 2 is a protein that in humans is encoded by the USP39 gene.-Further reading:...
, USP40USP40Ubiquitin carboxyl-terminal hydrolase 40 is an enzyme that in humans is encoded by the USP40 gene.-Further reading:...
, USP41, USP42USP42Ubiquitin carboxyl-terminal hydrolase 42 is an enzyme that in humans is encoded by the USP42 gene.-Further reading:...
, USP43, USP44USP44Ubiquitin carboxyl-terminal hydrolase 44 is an enzyme that in humans is encoded by the USP44 gene.-Further reading:...
, USP45, USP46) - the ubiquitin C-terminal hydrolyase (UCH) superfamily; (UCHH2, UCHL1, UCHL3UCHL3Ubiquitin carboxyl-terminal hydrolase isozyme L3 is an enzyme that in humans is encoded by the UCHL3 gene.-Interactions:UCHL3 has been shown to interact with NEDD8 and the tauopathy and synucleinopathy associated mutated ubiquitin molecule UBB+1....
) - the ovarian tumour (OTU) superfamily;
- and the Machado-Josephin domain (MJD) superfamily. (OTUB1OTUB1Ubiquitin thioesterase OTUB1 also known as otubain-1 is an enzyme that in humans is encoded by the OTUB1 gene. Alternative splicing results in multiple transcript variants.- Function :...
, OTUB2OTUB2Ubiquitin thioesterase OTUB2 is an enzyme that in humans is encoded by the OTUB2 gene.-Further reading:...
, ATXN3, ATXN3L)
However, there is also a little known putative group of DUBs called the permutated papain fold peptidases of dsDNA viruses and eukaryote (PPPDEs) superfamily, which, if shown to be bona fide DUBs, would be the fifth in the cysteine protease class.
Metalloproteases
The Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain superfamily proteins bind zinc and hence are metalloproteases.Role in the ubiquitin pathway
DUBs play several roles in the ubiquitin pathway. First, DUBs carry out activation of the ubiquitin proproteins, probably cotranslationally. Second, DUBs recycle ubiquitin that may have been accidentally trapped by the reaction of small cellular nucleophiles with the thiol ester intermediates involved in the ubiquitination of proteins. Third, DUBs reverse the ubiquitination or ubiquitin-like modification of target proteins. Fourth, DUBs are also responsible for the regeneration of monoubiquitin from unanchored polyubiquitin, i.e., free polyubiquitin that is synthesized de novo by the conjugating machinery or that has been released from target proteins by other DUBs. Finally, the deubiquitinating enzymes UCH-L3 and YUH1 are able to hydrolyse mutant ubiquitin UBB+1UBB+1
UBB+1 is shorthand for Ubiquitin-B+1, a frameshifted mutant arising from the Ubiquitin B gene. UBB+1 is thought to arise from molecular misreading, a poorly understood process. Molecular misreading introduces dinucleotide deletions into mRNA transcripts. These deletions are not present in...
despite of the fact that the glycine at position 76 is mutated.
Domain architecture
All DUBs contain a catalytic domainProtein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain. The DUSP domain displays a tripod-like AB3 fold
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
with a three-helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
bundle and a three-stranded anti-parallel beta-sheet resembling the legs and seat of the tripod. Conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
residues
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
are predominantly involved in hydrophobic packing interactions within the three alpha-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. The most conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
DUSP residues, forming the PGPI motif, are flanked by two long loops that vary both in length and sequence
Sequence (biology)
A sequence in biology is the one-dimensional ordering of monomers, covalently linked within in a biopolymer; it is also referred to as the primary structure of the biological macromolecule.-See also:* Protein sequence* DNA sequence...
. The PGPI motif packs against the three-helix bundle and is highly ordered. The function of the DUSP domain is unknown but it may play a role in protein/protein interaction or substrate recognition.