Multiple functions of BCL-2 family proteins

Abstract

BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.

Figure 1.

Human, C. elegans, and Drosophila BCL-2 family members. BH motifs are numbered, BH4 (light gray, unnumbered box indicates traditional classification without verified sequence homology), BH3 (black), BH1-BH2 (white), transmembrane (dark gray), arrows (protease cleavage sites). Splice variants (isoforms) are shown as separate or partially overlapped diagrams. Scale bar at the bottom marks increments of 50 amino acids.

Figure 2.

Map of key BCL-x_L mutants. Amino acid positions and single amino acid changes are indicated. tm, transmembrane region.

Figure 3.

Neuronal functions of BCL-2 family proteins in healthy cells.

Figure 4.

Viral BCL-2 family proteins with and without significant amino acid sequence similarity. BCL-2 family assignment of viral proteins are based on three-dimensional structure determinations or predicted structures. These proteins are found in the three large DNA virus families of mammals as indicated, although some lack detectable activities related to apoptosis (yellow boxes). See Figure 1 legend for BH motif key.