JAMM: a metalloprotease-like zinc site in the proteasome and signalosome.
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.
Ambroggio
Xavier I
XI
Division of Biology, California Institute of Technology, Pasadena, California, USA.
Rees
Douglas C
DC
Deshaies
Raymond J
RJ
D020816:Amino Acid Motifs; D000818:Animals; D001105:Archaea / Q000378:metabolism; D019611:Archaeoglobus fulgidus / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D045726:Metalloproteases / Q000737:chemistry*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D000075687:NEDD8 Protein; D016366:Open Reading Frames; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D015398:Signal Transduction; D013820:Thermolysin / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry; D014452:Ubiquitins / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
D004268:DNA-Binding Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D014157:Transcription Factors; D014452:Ubiquitins; D001224:Aspartic Acid; D018698:Glutamic Acid; D006639:Histidine; D045726:Metalloproteases; D013820:Thermolysin; D046988:Proteasome Endopeptidase Complex; D015032:Zinc