Figure 2.

Domain structure of the A20 protein. The amino terminus of A20 contains an ovarian tumor (OTU) domain, which has deubiquitinating enzyme (DUB) activity relying on the catalytic residue Cys103. The carboxy-terminal part of A20 contains seven zinc finger (ZnF) domains. The fourth ZnF domain has K63-linked polyubiquitin-binding affinity and possesses E3 ubiquitin (Ub) ligase activity, whereas the seventh ZnF domain has strong binding affinity for linear (M1) Ub chains. IKK2-mediated phosphorylation of A20 at Ser381 enhances the DUB activity of A20 toward K63-linked polyubiquitin. MALT1 cleaves A20 at Ala439 in human, or between the third and fourth ZnF domains in mouse. Mutations that were introduced to generate OTU (C103A), ZnF4 (C609A, C612A), or ZnF7 (C764A, C767A) domain-specific mutant mice are depicted by red stars. Both the OTU and ZnF4 domains have been shown to bind to E2 enzymes Ubc13 and UbcH5c.