Structural perspectives on BCL-2 family of proteins

BCL-2 proteins are a family of pro- and anti-apoptotic proteins that regulate a critical step in the mitochondrial apoptotic pathway, the permeabilization of the mitochondrial outer membrane. Because apoptosis and mitochondrial function play an important role in physiology and a number of diseases, intensive investigation over the past two decades has been invested to understand in detail the structure and function of the BCL-2 proteins. Structural biology investigations of BCL-2 proteins have provided tremendous insights into our understanding of their structure-function relationships and models have been proposed to explain how the BCL-2 family members form a network of interactions to control apoptosis signaling. Here, we will review the available structural information of pro- and anti-apoptotic members and the structures of their interaction in homodimerization and heterodimerization. We will discuss the structural insights for each structural domain of BCL-2 proteins that determine their function in the cytosol and the outer mitochondrial membrane. Furthermore, we will discuss the structural details of the interactions between BCL-2 family members and the various structural paradigms that ultimately regulate the activation of apoptosis.