S-nitrosylation of XIAP at Cys213 of BIR2 domain impairs XIAP's anti-caspase-3 activity

Abstract

XIAP is the most widely expressed IAP and plays an important role in regulating cell survival. XIAP contains three baculoviral IAP repeats (BIRs) domain and a RING domain. BIR domains provide XIAP anticaspase activities whereas RING functions as an E3 ligase. S-nitrosylation is a reversible post-translational modification of proteins by adding a nitric oxide to the thiol group of cysteine residue, which regulates a number of cellular processes. Our previous study found that XIAP can be S-nitrosylated at BIR domain and affect its anti-caspase activity. However, another study suggested S-nitrosylation of XIAP is through the RING domain, which affect its E3 ligase activity. In order to figure out the mechanism through which S-nitrosylation affect XIAP's anti-apoptotic function, I performed mutagenesis study and found that Cys213 of BIR2 is the critical cysteine residue for XIAP S-nitrosylation. Amino acid substitution of Cys213 diminished the S-nitrosylation of XIAP. The mutant protein XIAP-C213H was not affected by NO treatment in its anti-apoptosis function. These results confirmed the importance of one critical cysteine residue (Cys213) in XIAP S-nitrosylation and S-nitrosylation-induced loss of anti-caspase function. These findings will help understand how nitrosative stress contributes to PD pathogenesis through affecting prosurvival proteins such as XIAP.

Date of Award	2013
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology