title: Discoveries and controversies in BCL-2 protein-mediated apoptosis.
abstract: B-cell lymphoma 2 (BCL-2) family proteins mediate mitochondrial apoptosis by regulating mitochondrial outer membrane permeabilization (MOMP), which leads to the activation of the downstream caspase cascade to execute apoptosis. The pro-apoptotic and anti-apoptotic BCL-2 proteins function through protein-protein interactions in soluble and membrane-associated states. How soluble BCL-2 proteins interact is well understood. Anti-apoptotic proteins, such as BCL-2 and BCL-xL, and the pro-apoptotic effectors of MOMP, including BAK and BAX, interact with pro-apoptotic BCL-2 homology 3 (BH3)-only proteins similarly. Whereas anti-apoptotic BCL-2 proteins tightly bind all the BH3-only proteins to block apoptosis initiation, the effector BCL-2 proteins are potently triggered by specific BH3-only proteins to undergo conformational changes, membrane association and insertion, oligomerization, and pore formation. The anti-apoptotic BCL-2 proteins also inhibit the activated effectors. p53 is a direct BAX activator inhibited by BCL-xL, defining a prototype non-canonical modulator of BCL-2 proteins-mediated MOMP. How BCL-2 proteins cooperate in the presence of membranes remains poorly understood, impeding our understanding of MOMP and apoptosis. Here, we highlight the latest structural views of MOMP by BCL-2 proteins.
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Janet H
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ariele
authors.initials: A
authors.lastname: Viacava Follis
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Tudor
authors.initials: T
authors.lastname: Moldoveanu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006801:Humans; D051336:Mitochondrial Membranes / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D010539:Permeability; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
keywords: B-cell lymphoma 2; BH3-only; anti-apoptotic; derepressor; direct activator; effector; mitochondrial apoptosis; mitochondrial outer membrane permeabilization; pro-apoptotic; sensitizer