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The Bcl-2 family: structures, interactions and targets for drug discovery

  • The Domains of Apoptosis and Inflammation
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Abstract

Two phylogenetically and structurally distinct groups of proteins regulate stress induced intrinsic apoptosis, the programmed disassembly of cells. Together they form the B cell lymphoma-2 (Bcl-2) family. Bcl-2 proteins appeared early in metazoan evolution and are identified by the presence of up to four short conserved sequence blocks known as Bcl-2 homology (BH) motifs, or domains. The simple BH3-only proteins bear only a BH3-motif and are intrinsically disordered proteins and antagonize or activate the other group, the multi-motif Bcl-2 proteins that have up to four BH motifs, BH1-BH4. Multi-motif Bcl-2 proteins are either pro-survival or pro-apoptotic in action and have remarkably similar α-helical bundle structures that provide a binding groove formed from the BH1, BH2, and BH3-motifs for their BH3-bearing antagonists. In mammals a network of interactions between Bcl-2 members regulates mitochondrial outer membrane permeability (MOMP) and efflux of cytochrome c and other death inducing factors from mitochondria to initiate the apoptotic caspase cascade, but the molecular events leading to MOMP are uncertain. Dysregulation of the Bcl-2 family occurs in many diseases and pathogenic viruses have assimilated pro-survival Bcl-2 proteins to evade immune responses. Their role in disease has made the Bcl-2 family the focus of drug design attempts and clinical trials are showing promise for ‘BH3-mimics’, drugs that mimic the ability of BH3-only proteins to neutralize selected pro-survival proteins to induce cell death in tumor cells. This review focuses on the structural biology of Bcl-2 family proteins, their interactions and attempts to harness them as targets for drug design.

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Acknowledgments

Our research is supported by the National Health and Medical Research Council of Australia (Project APP1007918 to MK) and the Australian Research Council of Australia (Fellowship FT130101349 to MK).

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The authors declare no conflict of interest.

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  1. La Trobe Institute for Molecular Science, La Trobe University, Bundoora, 3086, Australia

    Marc Kvansakul

  2. School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3010, Australia

    Mark G. Hinds

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Kvansakul, M., Hinds, M.G. The Bcl-2 family: structures, interactions and targets for drug discovery. Apoptosis 20, 136–150 (2015). https://doi.org/10.1007/s10495-014-1051-7

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