Diablo homolog (DIABLO) (DIABLO)

Diablo homolog (DIABLO), also known as SMAC, is a mitochondrial protein encoded by the DIABLO gene on chromosome 12q24.31 that promotes apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2. Normally localized in the mitochondrial intermembrane space, DIABLO is released into the cytosol during apoptosis following mitochondrial outer membrane permeabilization, where its mature N-terminal Ala-Val-Pro-Ile (AVPI) tetrapeptide motif binds the BIR domains of IAPs, thereby relieving their inhibition of caspases and enabling caspase activation via the cytochrome c/Apaf-1/caspase-9 pathway. The protein functions as an arch-shaped homodimer, with dimerization essential for optimal IAP binding, particularly to the BIR2 domain. In disease, DIABLO overexpression sensitizes various tumor cells to apoptosis, making it relevant across cancers including breast, lung, colorectal, and others, while mutations are linked to nonsyndromic deafness. Therapeutically, small-molecule SMAC mimetics have been developed to replicate DIABLO's IAP-binding function, enhancing apoptosis in cancer treatments, though non-apoptotic roles remain unclear.

Other names

SMACsecond mitochondria-derived activator of caspasesdirect IAP-binding protein with low pIDFNA64

Mimicking the N-terminal AVPI motif to bind BIR3 domains of IAPs (XIAP, cIAP1, cIAP2), relieving caspase inhibition and promoting apoptosis (sometimes necroptosis)