Metalloprotease DUBs

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). <br><br>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).

JAB1/MPN+/MOV34（JAMM）结构域金属蛋白酶切割位于多泛素化底物连接点附近或其处的异肽键。PSMD14（RPN11）、STAMBP（AMSH）、STAMBPL1（AMSH-LP）和BRCC3（BRCC36）对K63多聚泛素连接具有高度特异性，这可能是其一般特征（Eletr & Wilkinson 2014）。Reactome中其他地方描述的两个多亚基复合体包含JAMM去泛素化酶。蛋白酶体19S盖状复合体包括PSMD14，一种内肽酶，在蛋白酶体降解底物时从底物中切割多泛素链（Verma et al. 2002）。COP9-信号体包含COPS5（CSN5），它去连接类似泛素的修饰物Nedd8，调节SCF E3连接酶的活性（Cope et al. 2002）。JAMM去泛素化酶的催化过程需要通过Zn2+结合的激活水分子和保守的谷氨酸对异肽键的羰基碳进行亲核攻击。随后形成带负电的四面体过渡态，而JAMM结构域中附近的保守丝氨酸/苏氨酸稳定了氧阴离子。四面体中间体随后塌陷，谷氨酸作为通用碱向离去赖氨酸侧链捐赠一个质子（Ambroggio et al. 2004）。