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PMID: 16905103 Published · ppublish English Comparative Study Journal Article

Structural basis of ubiquitin recognition by the deubiquitinating protease USP2.

Structure (London, England : 1993) ·Vol. 14 ·No. 8 ·2006-08-00 ·Pages 1293-302

Renatus M, Parrado SG, D'Arcy A, Eidhoff U, Gerhartz B, Hassiepen U, Pierrat B, Riedl R, Vinzenz D, Worpenberg S, Kroemer M

Abstract

Deubiquitinating proteases reverse protein ubiquitination and rescue their target proteins from destruction by the proteasome. USP2, a cysteine protease and a member of the ubiquitin specific protease family, is overexpressed in prostate cancer and stabilizes fatty acid synthase, which has been associated with the malignancy of some aggressive prostate cancers. Here, we report the structure of the human USP2 catalytic domain in complex with ubiquitin. Ubiquitin uses two major sites for the interaction with the protease. Both sites are required simultaneously, as shown by USP2 inhibition assays with peptides and ubiquitin mutants. In addition, a layer of ordered water molecules mediates key interactions between ubiquitin and USP2. As several of those molecules are found at identical positions in the previously solved USP7/ubiquitin-aldehyde complex structure, we suggest a general mechanism of water-mediated ubiquitin recognition by USPs.

MeSH Terms
Amino Acid Sequence Crystallization DNA Primers Endopeptidases/chemistry,genetics,metabolism Humans Kinetics Metals/metabolism Models, Molecular Molecular Sequence Data Protein Structure, Tertiary Ubiquitin/chemistry,metabolism Ubiquitin Thiolesterase Water/metabolism
Chemicals
DNA Primers Metals Ubiquitin Water Endopeptidases USP2 protein, human Ubiquitin Thiolesterase
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Renatus Martin
Protease Platform, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland. martin.renatus@novartis.com
Parrado Shirley Gil
D'Arcy Allan
Eidhoff Ulf
Gerhartz Bernd
Hassiepen Ulrich
Pierrat Benoit
Riedl Ralph
Vinzenz Daniela
Worpenberg Susanne
Kroemer Markus
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
0969-2126
DOI
10.1016/j.str.2006.06.012
Email
martin.renatus@novartis.com
Published
2006-08-00
Pages
1293-302
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC7126176
Subset
IM
Databases
PDB
2HD5, RCSB038216
External Links
PubMed source DOI: 10.1016/j.str.2006.06.012 PMC Full Text View journal details
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