The Bcl-2 family: structures, interactions and targets for drug discovery.
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.
La Trobe Institute for Molecular Science, La Trobe University, Bundoora, 3086, Australia, M.Kvansakul@latrobe.edu.au.
Marc
M
Kvansakul
Mark G
MG
Hinds
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000502:physiology*
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2