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Public Library of Science, PLoS Biology, 1(2), p. e2, 2003

DOI: 10.1371/journal.pbio.0020002

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

Journal article published in 2003 by Xavier I. Ambroggio, Douglas C. Rees, Raymond J. Deshaies ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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 EX(n)HS/THX(7)SXXD 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.