Structure and Function of IAP and Bcl‐2 Proteins

Abstract

Interactions between pro‐apoptotic and pro‐survival proteins control the apoptotic programme in cells. Regulation of caspases, the proteolytic enzymes that destroy the cell, is critical and the actions of the inhibitor of apoptosis (IAP) and B‐cell lymphoma‐2 (Bcl‐2) proteins control the life–death switch. IAP proteins can inhibit caspases and signal the destruction of regulatory molecules. In contrast, in mammals, the Bcl‐2 family controls mitochondrial integrity and the release of factors that activate caspases or block the action of IAPs. Structures of many of these proteins, and the complexes they form, are now available and underpin current models of apoptosis. Here we review key features of these structures and highlight how these studies have led to the development of antagonist compounds that allow the pro‐survival effects of IAP and Bcl‐2 proteins to be negated. Key Concepts Caspases are kept inactive in healthy cells by the actions of molecules that inhibit their oligomerization and processing. Pro‐survival Bcl‐2 proteins have a hydrophobic BH3‐binding groove that is required for binding both pro‐apoptotic BH3‐only and Bax‐like proteins. Bcl‐2 proteins exhibit conformational plasticity and can adopt distinct conformations that are required for their activity. The IBM‐binding site on the BIR domains is required for direct inhibition of caspases by IAPs. The RING domain of IAP proteins mediates their ubiquitin E3‐ligase activity, and is required for the pro‐apoptotic activity of IAP‐antagonist molecules. Structures of molecules that prevent caspase activation, in complex with their inhibitors, have guided the development of antagonist compounds that have therapeutic potential.