Cellular inhibitor of apoptosis protein 2 baculovirus IAP repeat 2 domain (cIAP2 BIR2)

Cellular inhibitor of apoptosis protein 2 (cIAP2), encoded by the BIRC3 gene, is a multi-domain protein that serves as a critical regulator of programmed cell death and inflammatory signaling pathways [1, 2]. The Baculovirus IAP Repeat 2 (BIR2) domain is one of three zinc-binding motifs in cIAP2 that mediate protein-protein interactions, specifically binding to IAP-binding motif (IBM)-containing proteins like SMAC/DIABLO [2, 3]. In many malignancies, such as MALT lymphoma and multiple myeloma, cIAP2 is overexpressed or mutated, leading to the evasion of apoptosis and the promotion of constitutive survival signaling through the NF-kappaB pathway [2, 4]. Therapeutic targeting of the BIR2 domain is primarily achieved using SMAC mimetics, which are small molecules designed to mimic the endogenous antagonist SMAC. These drugs bind to the BIR2 and BIR3 domains, triggering the E3 ligase activity of cIAP2 and inducing its rapid autoubiquitination and degradation [3]. This process sensitizes tumor cells to apoptosis-inducing stimuli, particularly TNF-alpha, making the cIAP2 BIR2 domain a high-interest target for oncology drug development [2, 4].

Other names

BIRC3 BIR2 domainBaculoviral IAP repeat-containing protein 3 BIR2 domainAPI2 BIR2 domainHIAP1 BIR2 domainMammalian IAP homolog C BIR2 domainInhibitor of apoptosis protein 2 BIR2 domain

SMAC mimetics bind to the BIR2 and BIR3 domains of cIAP2, mimicking the N-terminal IAP-binding motif of the endogenous protein SMAC/DIABLO. This binding induces a conformational change in cIAP2 that activates its RING domain E3 ligase activity, leading to rapid autoubiquitination and proteasomal degradation of the protein. The depletion of cIAP2 results in the stabilization of NIK, activation of the non-canonical NF-kappaB pathway, and sensitization of cells to TNF-alpha-induced apoptosis by facilitating the formation of pro-apoptotic signaling complexes.