Ubiquitin specific protease 4 (USP4) is an enzyme that cleaves ubiquitin from a number of protein substrates.[5] Prior to the standardization of nomenclature USP4 was known as UNP, and was one of the first deubiquitinating enzymes to be identified in mammals.[6] In the mouse and human the USP4 protein is encoded by a gene containing 22 exons.[7][8][9]

USP4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesUSP4, UNP, Unph, ubiquitin specific peptidase 4
External IDsOMIM: 603486; MGI: 98905; HomoloGene: 20716; GeneCards: USP4; OMA:USP4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_199443
NM_001251877
NM_003363

NM_011678
NM_001311157

RefSeq (protein)

NP_001238806
NP_003354
NP_955475

NP_001298086
NP_035808

Location (UCSC)Chr 3: 49.28 – 49.34 MbChr 9: 108.23 – 108.27 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

This protein is a member of cysteine peptidase family C19. As a deubiquitinating enzyme it is unusual in having the capacity to cleave ubiquitin-proline bonds.[10] This property may reflect structural flexibility in the active site of the enzyme, and may explain its ability to cleave ubiquitin chains of various linkages. USP4 has substrates of important function in a number of cell signalling pathways, including the NF-κB, TGF-β, Wnt/β-catenin, p53, and spliceosome pathways. Other substrates include the adenosine A2A receptor and the Ro52 (TRIM21) protein.

USP4 is a nucleocytoplasmic shuttling protein that bears a functional nuclear localization signal (NLS) 766QPQKKKK772 and a nuclear export signal (NES) 133VEVYLLELKL142.[11] Those signals initiate the translocation of USP4 to the nucleus from the cytoplasm and vice versa, respectively. The proportion of cytoplasmic to nuclear USP4 pool varies depending on the cell type, the phase of cell cycle and the level of protein expression.[11]

Interactions

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USP4 has been shown to interact with the tumor suppressor pRb protein and the pocket-related proteins p107 and p130.[12]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000114316Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032612Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Gray D (2012). "Chapter 462". In Rawlings & Salvesen (ed.). Handbook of Proteolytic Enzymes (3rd ed.). Elsevier. ISBN 9780123822192.
  6. ^ Gupta K, Copeland NG, Gilbert DJ, Jenkins NA, Gray DA (August 1993). "Unp, a mouse gene related to the tre oncogene". Oncogene. 8 (8): 2307–10. PMID 8336951.
  7. ^ Di Fruscio M, Gilchrist CA, Baker RT, Gray DA (May 1998). "Genomic structure of Unp, a murine gene encoding a ubiquitin-specific protease". Biochim. Biophys. Acta. 1398 (1): 9–17. doi:10.1016/s0167-4781(98)00035-9. PMID 9602026.
  8. ^ Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (July 2003). "Human and mouse proteases: a comparative genomic approach". Nat Rev Genet. 4 (7): 544–558. doi:10.1038/nrg1111. PMID 12838346. S2CID 2856065.
  9. ^ "Entrez Gene: USP4 ubiquitin specific peptidase 4 (proto-oncogene)".
  10. ^ Gilchrist CA, Gray DA, Baker RT (December 1997). "A ubiquitin-specific protease that efficiently cleaves the ubiquitin-proline bond". J. Biol. Chem. 272 (51): 32280–5. doi:10.1074/jbc.272.51.32280. hdl:2292/60433. PMID 9405433.
  11. ^ a b Soboleva, Tatiana A.; Jans, David A.; Johnson-Saliba, Melanie; Baker, Rohan T. (2004-10-18). "Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme". Journal of Biological Chemistry. 280 (1): 745–752. doi:10.1074/jbc.m401394200. ISSN 0021-9258. PMID 15494318.
  12. ^ Blanchette, Paola; Gilchrist, Catherine A; Baker, Rohan T; Gray, Douglas A (September 2001). "Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130". Oncogene. 20 (39): 5533–5537. doi:10.1038/sj.onc.1204823. ISSN 0950-9232. PMID 11571651.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: Q13107 (Ubiquitin carboxyl-terminal hydrolase 4) at the PDBe-KB.