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JAMM: A Metalloprotease-Like Zinc Site in the Proteasome and Signalosome

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Title JAMM: A Metalloprotease-Like Zinc Site in the Proteasome and Signalosome
 
Creator Ambroggio, Xavier I.
Rees, Douglas C.
Deshaies, Raymond J.
 
Subject Caltech Library Services
 
Description The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the
proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EXnHS/THX7SXXD motif coordinate a zinc, whereas the glutamic acid hydrogen-bonds an aqua ligand. By analogy to the active
site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors.
 
Publisher Public Library of Science
 
Date 2004-01
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://authors.library.caltech.edu/261/1/AMBpb04.pdf
Ambroggio, Xavier I. and Rees, Douglas C. and Deshaies, Raymond J. (2004) JAMM: A Metalloprotease-Like Zinc Site in the Proteasome and Signalosome. PLoS Biology, 2 (1). pp. 113-119. ISSN 1544-9173. PMCID PMC300881. http://resolver.caltech.edu/CaltechAUTHORS:AMBpb04 <http://resolver.caltech.edu/CaltechAUTHORS:AMBpb04>
 
Relation http://resolver.caltech.edu/CaltechAUTHORS:AMBpb04
http://authors.library.caltech.edu/261/