We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
JAMM: A Metalloprotease-Like Zinc Site in the Proteasome and Signalosome.
- Authors
Ambroggio, Xavier I.; Rees, Douglas C.; Deshaies, Raymond J.; Ploegh, Hidde L.
- 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[subn]HS/THX[sub7]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.
- Subjects
PEPTIDASE; PROTEOLYTIC enzymes; PROTEINS; METALLOPROTEINASES; LIGANDS (Biochemistry); ASPARTIC acid; SERINE
- Publication
PLoS Biology, 2004, Vol 2, Issue 1, p0001
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal/pbio.0020002