JAMM domain zinc metalloprotease (JAMM (JAB1/MPN/Mov34 metalloenzyme))

The JAMM domain zinc metalloprotease is a unique class of deubiquitinating enzymes (DUBs) characterized by a zinc-dependent metalloprotease mechanism and a conserved sequence motif (EX(n)HS/THX(7)SXXD). These enzymes are critical in the removal of ubiquitin (and ubiquitin-like proteins such as NEDD8) from substrate proteins, a process essential for regulating the ubiquitin-proteasome pathway, protein turnover, and proteasome activity. The JAMM domain (also known as the JAB1/MPN/Mov34 motif) is found in multiple essential eukaryotic proteins, such as Rpn11 (in the 19S proteasome) and Csn5 (in the COP9 signalosome), where it orchestrates the terminal steps of protein degradation by removing ubiquitin prior to substrate proteolysis[6][4][1]. The mechanism involves catalytic hydrolysis of the isopeptide bond via a zinc-mediated nucleophilic attack, similar to but structurally distinct from classical thermolysin-like metalloproteases[1][3][6]. Dysregulation and mutation of JAMM domain proteins are implicated in tumorigenesis and other disorders, making the JAMM domain an actively pursued therapeutic target in oncology and immunology, with small-molecule inhibitors under development[4][6][1].

Other names

JAB1/MPN/Mov34 metalloenzymeMPN+ isopeptidaseJAMM motif proteaseZn^2+-dependent JAMM metalloproteaseJAMM metalloprotease

Competitive inhibition at the catalytic zinc site of the JAMM domain; Coordination or chelation of Zn^2+ in the active site to block enzymatic activity; Interference with protein deubiquitination/deNEDDylation, thereby affecting protein degradation pathways