X-linked inhibitor of apoptosis protein (XIAP) (XIAP)

X-linked inhibitor of apoptosis protein (XIAP) is a potent endogenous suppressor of programmed cell death and a member of the inhibitor of apoptosis (IAP) family (UniProt P98170). It is characterized by three Baculovirus IAP Repeat (BIR) domains and a C-terminal RING finger domain, which confers E3 ubiquitin ligase activity. XIAP uniquely inhibits apoptosis by directly binding and neutralizing initiator caspase-9 via its BIR3 domain and effector caspases-3 and -7 via its BIR2 domain and the preceding linker (PubMed: 11084022). Beyond its anti-apoptotic role, XIAP modulates inflammatory signaling pathways, including NF-kappaB and MAP kinase, and plays a role in copper metabolism (PubMed: 21654818). In many human malignancies, XIAP is overexpressed, which is associated with tumor progression, poor prognosis, and resistance to chemotherapy and radiation (PubMed: 24469444). Therapeutic targeting of XIAP primarily involves SMAC mimetics, small molecules that bind to the BIR domains to displace caspases and promote the degradation of IAP proteins, thereby restoring apoptotic sensitivity in cancer cells.

Other names

Baculoviral IAP repeat-containing protein 4BIRC4IAP3API3X-linked IAPInhibitor of apoptosis protein 3

SMAC mimetics (IAP antagonists) bind to the BIR2 and BIR3 domains of XIAP, mimicking the N-terminal IAP-binding motif of the endogenous protein SMAC/DIABLO. This competitive binding prevents XIAP from interacting with and inhibiting caspases-3, -7, and -9, thereby restoring the apoptotic cascade. Additionally, these agents can induce a conformational change in IAPs that triggers RING-domain-mediated autoubiquitination and subsequent proteasomal degradation (PubMed: 24469444, 17706774).