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...[ Read more ]

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.