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2foj, resolution 1.60Å ()
Gene: USP7, HAUSP (Homo sapiens)
Activity: Ubiquitin thiolesterase, with EC number
Related: 1yy6, 1yze, 2foo, 2fop
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


The Crystal Strucure of the N-terminal domain of HAUSP/USP7 complexed with p53 peptide 364-367

Publication Abstract from PubMed

The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby it stabilizes both p53 and MDM2. We show that the N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2, falling between p53 residues 359-367 and MDM2 residues 147-159. Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide. These peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1, explaining the competitive nature of the interactions. The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7. Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway.

Molecular recognition of p53 and MDM2 by USP7/HAUSP., Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith CH, Frappier L, Nat Struct Mol Biol. 2006 Mar;13(3):285-91. Epub 2006 Feb 12. PMID:16474402

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.


[UBP7_HUMAN] Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Exhibits a preference towards 'Lys-48'-linked Ubiquitin chains.[1][2][3][4][5][6][7][8][9][10][11][12][13]

About this Structure

2foj is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.


  • Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith CH, Frappier L. Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol. 2006 Mar;13(3):285-91. Epub 2006 Feb 12. PMID:16474402 doi:http://dx.doi.org/10.1038/nsmb1067
  1. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature. 2002 Apr 11;416(6881):648-53. Epub 2002 Mar 31. PMID:11923872 doi:10.1038/nature737
  2. Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L. Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP. J Biol Chem. 2003 Nov 28;278(48):47753-61. Epub 2003 Sep 23. PMID:14506283 doi:10.1074/jbc.M307200200
  3. Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004 Mar 26;13(6):879-86. PMID:15053880
  4. Boutell C, Canning M, Orr A, Everett RD. Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7. J Virol. 2005 Oct;79(19):12342-54. PMID:16160161 doi:10.1128/JVI.79.19.12342-12354.2005
  5. van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol. 2006 Oct;8(10):1064-73. Epub 2006 Sep 10. PMID:16964248 doi:10.1038/ncb1469
  6. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature. 2008 Oct 9;455(7214):813-7. doi: 10.1038/nature07290. Epub 2008 Aug 20. PMID:18716620 doi:10.1038/nature07290
  7. Antrobus R, Boutell C. Identification of a novel higher molecular weight isoform of USP7/HAUSP that interacts with the Herpes simplex virus type-1 immediate early protein ICP0. Virus Res. 2008 Oct;137(1):64-71. doi: 10.1016/j.virusres.2008.05.017. Epub 2008 , Jul 17. PMID:18590780 doi:10.1016/j.virusres.2008.05.017
  8. Tang J, Qu L, Pang M, Yang X. Daxx is reciprocally regulated by Mdm2 and Hausp. Biochem Biophys Res Commun. 2010 Mar 12;393(3):542-5. doi:, 10.1016/j.bbrc.2010.02.051. Epub 2010 Feb 12. PMID:20153724 doi:10.1016/j.bbrc.2010.02.051
  9. Felle M, Joppien S, Nemeth A, Diermeier S, Thalhammer V, Dobner T, Kremmer E, Kappler R, Langst G. The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1. Nucleic Acids Res. 2011 Oct;39(19):8355-65. doi: 10.1093/nar/gkr528. Epub 2011, Jul 10. PMID:21745816 doi:10.1093/nar/gkr528
  10. Ma H, Chen H, Guo X, Wang Z, Sowa ME, Zheng L, Hu S, Zeng P, Guo R, Diao J, Lan F, Harper JW, Shi YG, Xu Y, Shi Y. M phase phosphorylation of the epigenetic regulator UHRF1 regulates its physical association with the deubiquitylase USP7 and stability. Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4828-33. doi:, 10.1073/pnas.1116349109. Epub 2012 Mar 12. PMID:22411829 doi:10.1073/pnas.1116349109
  11. Iphofer A, Kummer A, Nimtz M, Ritter A, Arnold T, Frank R, van den Heuvel J, Kessler BM, Jansch L, Franke R. Profiling ubiquitin linkage specificities of deubiquitinating enzymes with branched ubiquitin isopeptide probes. Chembiochem. 2012 Jul 9;13(10):1416-20. doi: 10.1002/cbic.201200261. Epub 2012, Jun 11. PMID:22689415 doi:10.1002/cbic.201200261
  12. Schwertman P, Lagarou A, Dekkers DH, Raams A, van der Hoek AC, Laffeber C, Hoeijmakers JH, Demmers JA, Fousteri M, Vermeulen W, Marteijn JA. UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair. Nat Genet. 2012 May;44(5):598-602. doi: 10.1038/ng.2230. PMID:22466611 doi:10.1038/ng.2230
  13. Zhang X, Horibata K, Saijo M, Ishigami C, Ukai A, Kanno S, Tahara H, Neilan EG, Honma M, Nohmi T, Yasui A, Tanaka K. Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. Nat Genet. 2012 May;44(5):593-7. doi: 10.1038/ng.2228. PMID:22466612 doi:10.1038/ng.2228

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