Inhibitor of apoptosis protein–caspase and inhibitor of apoptosis protein–receptor-interacting protein kinase protein–protein interfaces (IAP–caspase / IAP–RIPK PPIs)

The Inhibitor of Apoptosis Protein (IAP)–caspase and IAP–Receptor-Interacting Protein Kinase (RIPK) protein–protein interfaces are critical regulatory nodes in the control of programmed cell death. IAPs, such as XIAP, cIAP1, and cIAP2, utilize their Baculovirus IAP Repeat (BIR) domains to physically interact with and inhibit pro-apoptotic caspases or to modulate the signaling scaffolds of RIPK1 within the Tumor Necrosis Factor (TNF) receptor complex (Eckelman et al., 2006, Cell Death & Differentiation). In many cancers, these proteins are overexpressed, allowing tumor cells to evade apoptosis and survive despite oncogenic stress or chemotherapy. Therapeutic intervention typically involves Smac mimetics, which are small molecules designed to mimic the endogenous IAP antagonist Smac/DIABLO. These agents bind to the BIR domains, effectively displacing caspases from XIAP and triggering the rapid degradation of cIAP1 and cIAP2 (Varfolomeev et al., 2007, Cell). This molecular shift promotes the formation of pro-apoptotic or necroptotic complexes, sensitizing tumor cells to death and modulating the inflammatory microenvironment.

Other names

IAP-caspase interfaceIAP-RIPK1 interfaceBIR domain-mediated interactionsSmac-binding siteIAP-IBM interface

Smac mimetics bind to the BIR2 and BIR3 domains of IAPs, mimicking the N-terminal IAP-binding motif (IBM) of Smac/DIABLO to displace caspases from XIAP and induce the autoubiquitination and proteasomal degradation of cIAP1 and cIAP2 (Fulda, 2015, Archives of Biochemistry and Biophysics).