Nakatani Y, Kleffmann T, Linke K, Condon SM, Hinds MG, Day CL

RING domains of E3 ligases promote transfer of ubiquitin (Ub) from the E2~Ub conjugate to target proteins. In many cases interaction of the E2~Ub conjugate with the RING domain requires its prior dimerization. Using cross-linking experiments we show that E2 conjugated ubiquitin contacts the RING homodimer interface of the Inhibitor ...

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of Apoptosis (IAP) proteins, XIAP and cIAP2. Structural and biochemical analysis of the XIAP RING dimer shows that an aromatic residue at the dimer interface is required for E2~Ub binding and ubiquitin transfer. Mutation of the aromatic residue abolishes ubiquitin transfer but not interaction with ubiquitin. This indicates that nuleophilic attack on the thioester bond depends on precise contacts between ubiquitin and the RING domain. RING dimerization is a critical activating step for the cellular IAP proteins. However, our analysis shows that the RING domain of XIAP forms a stable dimer and its E3 ligase activity does not require an activation step.

Date: Dec. 21, 2012

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