The JAB1/MPN +/MOV34 (JAMM) domain metalloproteases cleave the isopeptide bond at or near the the attachment point of polyubiquitin and substrate. PSMD14 (RPN11), STAMBP (AMSH), STAMBPL1 (AMSH-LP), and BRCC3 (BRCC36) are highly specific for the K63 poly-Ub linkage, which may be a general characteristic (Eletr & Wilkinson 2014). Two multisubunit complexes represented elsewhere in Reactome contain JAMM DUBs. The proteasome 19S lid complex includes PSMD14, an endopeptidase that cleaves poly-Ub chains from substrates as they are degraded by the proteasome (Verma et al. 2002). The COP9-Signalosome contains COPS5 (CSN5), which deconjugates the Ub-like modifier Nedd8, modulating the activity of the SCF E3 ligase (Cope et al. 2002).

JAMM DUB catalysis requires nucleophilic attack on the carbonyl carbon of the isopeptide bond by an activated water molecule bound to Zn2+ and a conserved glutamate. A negatively-charged tetrahedral transition state ensues, and a nearby conserved Ser/Thr in the JAMM domains stabilizes the oxyanion. The tetrahedral intermediate then collapses and the Glu serves as a general base donating a proton to the leaving Lys side chain (Ambroggio et al. 2004).