JAMM: A Metalloprotease-like zinc site in the proteasome and signalosome

Journal Article · Mon Jun 27 04:00:00 EDT 2005 · PLoS Biol.2:113,2004

OSTI ID:890284

Ambroggio, X I; Rees, D C; Deshaies, R J

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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 890284
• Report Number(s): SLAC-REPRINT-2004-289
• Journal Information: PLoS Biol.2:113,2004, Journal Name: PLoS Biol.2:113,2004
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ARCHITECTURE
ASPARTIC ACID
CATALYSTS
GLUTAMIC ACID
HISTIDINE
MUTAGENESIS
Other
OTHER
PROTEINS
RESIDUES
SERINE
ZINC