USP20
| Ubiquitin specific peptidase 20 | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | USP20; LSFR3A; VDU2; hVDU2 | ||||||||||||
| External IDs | OMIM: 615143 MGI: 1921520 HomoloGene: 4861 GeneCards: USP20 Gene | ||||||||||||
| EC number | 3.4.19.12 | ||||||||||||
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| RNA expression pattern | |||||||||||||
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| More reference expression data | |||||||||||||
| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 10868 | 74270 | |||||||||||
| Ensembl | ENSG00000136878 | ENSMUSG00000026854 | |||||||||||
| UniProt | Q9Y2K6 | Q8C6M1 | |||||||||||
| RefSeq (mRNA) | NM_001008563 | NM_028846 | |||||||||||
| RefSeq (protein) | NP_001008563 | NP_083122 | |||||||||||
| Location (UCSC) | Chr 9: 132.6 – 132.64 Mb | Chr 2: 30.98 – 31.02 Mb | |||||||||||
| PubMed search | |||||||||||||
Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.[1][2]
Ubiquitin-specific protease 20 (USP20), also known as ubiquitin-binding protein 20 and VHL protein-interacting deubiquitinating enzyme 2 (VDU2), is a cysteine protease deubiquitinating enzyme (DUB). The catalytic site of USP20, like other DUBs, contains conserved cysteine and histidine residues that catalyse the proteolysis of an isopeptide bond between a lysine residue of a target protein and a glycine residue of a ubiquitin molecule.[3] USP20 is known to deubiquitinate a number of proteins including thyronine deiodinase type 2 (D2), Hypoxia-inducible factor 1α (HIF1α), and β2 adrenergic receptor (β2AR).[4][5][6]
Gene
The USP20 gene is located on chromosome 9 at the locus 9q34.11.[2][7]
Structure
USP20 is a 914-amino acid protein that shows 59% homology with another DUB, USP33.[8] It contains 4 known domains, an N-terminal Zf UBP domain, a catalytic domain containing conserved histidine and cysteine residues, and two C-terminal DUSP domains.[9]
Function
DUBs are categorised into 5 main groups, ubiquitin-specific proteases (USP), ubiquitin c-terminal hydrolases (UCH), ovarian tumour proteases (OTU), Machado-Joseph disease proteases (MJD), and JAB1/MPN/MOV34 proteases (JAMM/MPN+). The first four groups are cysteine proteases, whereas the last group are Zn metalloproteases. USP20 belongs to the USP group and, like most DUBs, catalyse the breakage of an isopeptide bond between a lysine residue of the target protein and the terminal glycine residue of a ubiquitin protein. This occurs via a conserved cysteine and histidine residue in the catalytic site of the enzyme. The histidine molecule is protonated by the cysteine residue and this allows the cystein residue to undergo a nucleophillic attack on the isopeptide bond, which removes the ubiquitin from the substrate protein.[10]
Thyronine deiodinase type 2
USP20 deubiquitinates thyronine deiodinase type 2 (D2), an enzyme that converts thyroxine (T4) into active 3,5,3'-triiodothyronine (T3). D2 is ubiquitinated after binding of T4, which signals for the degradation of D2 via the proteasome and also causes an inactivating conformational change of the protein. Deubiquitination by USP20 rescues D2 from degradation and also returns D2 to its active conformation.[4][11]
Hypoxia inducible factor 1α
The von Hippel-Lindau tumour supressor protein (pVHL) ubiquitinates hypoxia-inducible factor 1α (HIF1α) when cell oxygen levels are normal. This leads to the degradation of HIF1α and prevents the transcription of hypoxic response genes such as vascular endothelial growth factor, platelet-derived growth factor B, and erythropoietin. USP20 deubiquitinates HIF1α, preventing its proteasomal degradation, and allows it to transcribe the hypoxic response genes.[12]
β2 adrenergic receptor
USP20 is involved in the recycling of the β2-adrenergic receptor. After agonist stimulation, the receptor is internalised and ubiquitinated. USP20 serves to deubiquitinate the receptor and prevent its degradation by the proteasome. This allows it to be recycled to the cell surface in order to resensitize the cell to signalling molecules.[6]
Regulation
In addition to the regulation of HIF1α, pVHL regulates USP20. USP20 binds to the β-domain of pVHL and is subsequently ubiquitinated. This signals USP20 for degradation via the proteasome.[8]
References
- ↑ Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (Jul 2003). "Human and mouse proteases: a comparative genomic approach". Nat Rev Genet 4 (7): 544–58. doi:10.1038/nrg1111. PMID 12838346.
- ↑ 2.0 2.1 "Entrez Gene: USP20 ubiquitin specific peptidase 20".
- ↑ Komander D, Clague MJ, Urbé S (August 2009). "Breaking the chains: structure and function of the deubiquitinases". Nat. Rev. Mol. Cell Biol. 10 (8): 550–63. doi:10.1038/nrm2731. PMID 19626045.
- ↑ 4.0 4.1 Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW, Li Z, Wu G, Bianco AC (July 2003). "Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation". J. Clin. Invest. 112 (2): 189–96. doi:10.1172/JCI18348. PMC 164294. PMID 12865408.
- ↑ Li Z, Wang D, Messing EM, Wu G (April 2005). "VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1α". EMBO Rep. 6 (4): 373–8. doi:10.1038/sj.embor.7400377. PMC 1299287. PMID 15776016.
- ↑ 6.0 6.1 Berthouze M, Venkataramanan V, Li Y, Shenoy SK (June 2009). "The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization". EMBO J. 28 (12): 1684–96. doi:10.1038/emboj.2009.128. PMC 2699358. PMID 19424180.
- ↑ "Genecards". Retrieved 10 October 2012.
- ↑ 8.0 8.1 Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G (June 2002). "Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor". Biochem. Biophys. Res. Commun. 294 (3): 700–9. doi:10.1016/S0006-291X(02)00534-X. PMID 12056827.
- ↑ de Jong RN, Ab E, Diercks T, Truffault V, Daniëls M, Kaptein R, Folkers GE (February 2006). "Solution structure of the human ubiquitin-specific protease 15 DUSP domain". J. Biol. Chem. 281 (8): 5026–31. doi:10.1074/jbc.M510993200. PMID 16298993.
- ↑ Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (December 2005). "A genomic and functional inventory of deubiquitinating enzymes". Cell 123 (5): 773–86. doi:10.1016/j.cell.2005.11.007. PMID 16325574.
- ↑ Daviet L, Colland F (February 2008). "Targeting ubiquitin specific proteases for drug discovery". Biochimie 90 (2): 270–83. doi:10.1016/j.biochi.2007.09.013. PMID 17961905.
- ↑ Kondo K, Kaelin WG (March 2001). "The von Hippel-Lindau tumor suppressor gene". Exp. Cell Res. 264 (1): 117–25. doi:10.1006/excr.2000.5139. PMID 11237528.
Further reading
- Nagase T, Ishikawa K, Suyama M, et al. (1999). "Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.". DNA Res. 6 (1): 63–70. doi:10.1093/dnares/6.1.63. PMID 10231032.
- Gilley J, Fried M (1999). "Extensive gene order differences within regions of conserved synteny between the Fugu and human genomes: implications for chromosomal evolution and the cloning of disease genes.". Hum. Mol. Genet. 8 (7): 1313–20. doi:10.1093/hmg/8.7.1313. PMID 10369878.
- Li Z, Wang D, Na X, et al. (2002). "Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor.". Biochem. Biophys. Res. Commun. 294 (3): 700–9. doi:10.1016/S0006-291X(02)00534-X. PMID 12056827.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Curcio-Morelli C, Zavacki AM, Christofollete M, et al. (2003). "Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation.". J. Clin. Invest. 112 (2): 189–96. doi:10.1172/JCI18348. PMC 164294. PMID 12865408.
- Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9.". Nature 429 (6990): 369–74. doi:10.1038/nature02465. PMC 2734081. PMID 15164053.
- Li Z, Wang D, Messing EM, Wu G (2005). "VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.". EMBO Rep. 6 (4): 373–8. doi:10.1038/sj.embor.7400377. PMC 1299287. PMID 15776016.
- Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.". Cell 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.