JAMM: a metalloprotease-like zinc site in the proteasome and signalosome |
| |
Authors: | Ambroggio Xavier I Rees Douglas C Deshaies Raymond J |
| |
Institution: | 1
Division of Biology, California Institute of Technology
Pasadena, California
United States of America;2
Division of Chemistry and Chemical Engineering, California Institute of Technology
Pasadena, California
United States of America;3
Howard Hughes Medical Institute, Chevy Chase
Maryland
United States of America |
| |
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 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
| 点击此处可从《PLoS Biology》浏览原始摘要信息 |
| 点击此处可从《PLoS Biology》下载免费的PDF全文 |