Bcl-2 Homodimerization Involves Two Distinct Binding Surfaces, a Topographic Arrangement That Provides an Effective Mechanism for Bcl-2 to Capture Activated Bax

The homo- and heterodimerization of Bcl-2 family proteins is important for transduction and integration of apoptotic signals and control of the permeability of mitochondria and endoplasmic reticulum membranes. Here we mapped the interface of the Bcl-2 homodimer in a cell-free system using site-specific photocross-linking. Bcl-2 homodimer-specific photoadducts were detected from 11 of 17 sites studied. When modeled into the structure of Bcl-2 core, the interface is composed of two distinct surfaces: an acceptor surface that includes the hydrophobic groove made by helices 2 and 8 and the loop connecting helices 4 and 5 and a donor surface that is made by helices 1-4 and the loop connecting helices 2 and 3. The two binding surfaces are on separate faces of the three-dimensional structure, explaining the formation of Bcl-2 homodimers, homo-oligomers, and Bcl-2/Bax hetero-oligomers. We show that in vitro the Bcl-2 dimer can still interact with activated Bax as a larger oligomer. However, formation of a Bax/Bcl-2 heterodimer is favored, since this interaction inhibits Bcl-2 homodimerization. Our data support a simple model mechanism by which Bcl-2 interacts with activated Bax during apoptosis in an effective manner to neutralize the proapoptotic activity of Bax. The homo- and heterodimerization of Bcl-2 family proteins is important for transduction and integration of apoptotic signals and control of the permeability of mitochondria and endoplasmic reticulum membranes. Here we mapped the interface of the Bcl-2 homodimer in a cell-free system using site-specific photocross-linking. Bcl-2 homodimer-specific photoadducts were detected from 11 of 17 sites studied. When modeled into the structure of Bcl-2 core, the interface is composed of two distinct surfaces: an acceptor surface that includes the hydrophobic groove made by helices 2 and 8 and the loop connecting helices 4 and 5 and a donor surface that is made by helices 1-4 and the loop connecting helices 2 and 3. The two binding surfaces are on separate faces of the three-dimensional structure, explaining the formation of Bcl-2 homodimers, homo-oligomers, and Bcl-2/Bax hetero-oligomers. We show that in vitro the Bcl-2 dimer can still interact with activated Bax as a larger oligomer. However, formation of a Bax/Bcl-2 heterodimer is favored, since this interaction inhibits Bcl-2 homodimerization. Our data support a simple model mechanism by which Bcl-2 interacts with activated Bax during apoptosis in an effective manner to neutralize the proapoptotic activity of Bax. Bcl-2 family proteins are key regulators of apoptosis. These proteins share sequence homology in Bcl-2 homology (BH) 1The abbreviations used are: BH, Bcl-2 homology; BMH, bis-maleimidohexane; ϵANB, Nϵ-(5-azido-2-nitrobenzoyl); FAK, focal adhesion kinase; PARP, poly(ADP-ribose) polymerase; WT, wild type; ANB, 5-azido-2-nitrobenzoyl.1The abbreviations used are: BH, Bcl-2 homology; BMH, bis-maleimidohexane; ϵANB, Nϵ-(5-azido-2-nitrobenzoyl); FAK, focal adhesion kinase; PARP, poly(ADP-ribose) polymerase; WT, wild type; ANB, 5-azido-2-nitrobenzoyl. domains and function to promote or prevent apoptosis. Anti-apoptotic proteins such as Bcl-2 and Bcl-xL show homology in four BH domains (BH1 to -4). Proapoptotic proteins can be grouped into “multidomain” and “BH3-only” subfamilies. Multidomain proapoptotic proteins such as Bax and Bak display homology in BH domains 1-3, whereas BH3-only proteins such as Bid and Bim are similar structurally to multidomain family members, but sequence similarity is limited to only the BH3 domain. The current model for how Bcl-2 family proteins regulate apoptosis involves three sequential processes: (i) BH3-only proteins are activated by various death signals; (ii) the active BH3-only proteins then either activate multidomain proapoptotic proteins or inhibit antiapoptotic proteins or both; and (iii) unless inhibited by antiapoptotic Bcl-2 proteins, activated multidomain proapoptotic proteins form oligomers in the mitochondrial outer membrane that release proapoptotic proteins such as cytochrome c and Smac/DIABLO from the mitochondrial intermembrane space. The released proteins trigger activation of the caspases and nucleases that eventually dismantle the cell (1Annis M.G. Yethon J.A. Leber B. Andrews D.W. Biochim. Biophys. Acta. 2004; 1644: 115-123Crossref PubMed Scopus (60) Google Scholar, 2Petros A.M. Olejnicizak E.T. Fesik S.W. Biochim. Biophys. Acta. 2004; 1644: 83-94Crossref PubMed Scopus (593) Google Scholar, 3Scorrano L. Korsmeyer S.J. Biochem. Biophys. Res. 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We that 17 or and are the dimer since photoadducts the two proteins, whereas and not in formation with the not the interface is not limited to the hydrophobic groove. the Bcl-2 data in 2 were used to model which be in the Bcl-2 homodimer on the structure of the Bcl-2 A.M. Medek A. Nettesheim D.G. Kim D.H. Yoon H.S. Swift K. Matayoshi E.D. Oltersdorf T. Fesik S.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3012-3017Crossref PubMed Scopus (357) Google Scholar). on the structure that are two distinct binding surfaces in the homodimer that we to as acceptor and donor surfaces A and in the acceptor surface is by photoadducts the the that are surface with the hydrophobic the that in Bcl-2 family protein The in the of the acceptor surface not to The donor surface is to the acceptor and the in photoadducts are surface on of helix a with the of this helix as the to the helix that to the hydrophobic acceptor groove on Bcl-xL M. Liang H. Nettesheim D. Meadows R.P. Harlan J.E. M. Yoon H.S. 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However, that the donor surface helix 2 into helices and the BH3 and the donor surface we is in the structure of Bcl-2 and does not a to helix 2 such that can form the binding is not of the donor surface Bcl-2 of model is that Bcl-2 form homo-oligomers, since Bcl-2 protein binding and of not be with this that proteins from a as and oligomers were The of dimer and to in the is that by the since and oligomers into during The not the proteins were in a and the used for in vitro for the and to not that a of Bcl-2 in in the of and Bax with Bcl-2 and the that Bcl-2 proteins can form and oligomers that two distinct binding how a proapoptotic Bcl-2 family such as interact with which of Bcl-2 or can be by we used in vitro that and Bax protein to The Bax protein a protein in and that the protein in a similar to that of Bax in J.A. Leber B. Andrews D.W. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Bax proteins in the and not with or with Bcl-2 family of Bax proteins are to an active and to mitochondrial and form or with Bcl-2 family Bax is to interact with the of Bcl-2 to form a since the C-terminal of Bcl-2 is in the and is not for the in photoadducts between the protein and Bax protein were The of the is with the formation of a the proteins were by the for Bax and were only Bax and were all 4 and used to the in vitro not for the formation of the Bcl-2/Bax heterodimer 4 with that can Bax to a Youle R.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). activated Bax can interact with Bcl-2 to form Bax/Bcl-2 is important to or not the activated Bax protein can interact with Bcl-2 homodimers, since of the Bcl-2 proteins from to be in homodimer or B. S. B. J.C. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Bax can interact with the Bcl-2 homodimer we used the to two proteins, a two the two are a for in a Bcl-2 homodimer the two binding surfaces we We detected dimer only in the of BMH, not the control and When a protein used in proteins were that the is and Bax can to the Bcl-2 homodimers, we the from the with in vitro Bax protein with to the on the of the photoadducts detected in the to between Bax and the dimer between Bax and were detected These are not Bax Bax not to the not similar to the Bax The by an is a of Bax oligomers with is that the includes or proteins from the that Bcl-2 and larger oligomers activated that of neutralize Bax apoptotic Bax to the of data support a model in which a Bcl-2 homodimer is by interaction of the acceptor surface of with the donor surface of Bcl-2/Bax heterodimer interface can be mapped in the However, of the various that we have only to Bax not is in the acceptor surface of Bcl-2 this that Bax the acceptor surface of with Bax binding to only the acceptor a Bcl-2 to the interaction between Bcl-2 and Bax Korsmeyer S.J. Nature. PubMed Scopus Google is in the of the acceptor surface that an interaction between Bcl-2 and Bax is not detected by we between in vitro with to and Bax. in by the the that the acceptor surface in Bcl-2 as the binding for Bax. since the not the of two proteins the in proteins the not homodimerization. with Bcl-2 to and in Korsmeyer S.J. Nature. PubMed Scopus Google Scholar, S.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the Bcl-2 homodimer interface be that of Bcl-2/Bax of Bcl-2 by that Bax can to a Bcl-2 homodimer that is with a that the homodimer an binding for as from However, binding of Bax to Bcl-2 Bcl-2 as by Milliman C.L. Korsmeyer S.J. Cell. Full Text PDF PubMed Scopus Google such an not be by this or not Bax binding to Bcl-2 inhibits Bcl-2 were with in vitro and in the of of Bax. in the of two proteins inhibited by the Bax in a the of between Bax and with the of Bax to the with the data in this that Bax/Bcl-2 interaction the of Bcl-2 homodimer by either binding to the Bcl-2 or binding to and the Bcl-2 dimer or Our that the interface of the Bcl-2 homodimer is from using The binding interface can be into acceptor and donor surfaces and includes of all four BH The acceptor of helix the loop between helix 4 and and helix includes the The donor surface that of helices the BH3 and is from the acceptor of the of the two binding surface does not the Bcl-2 can either Bax or Bcl-2 its acceptor surface and Bcl-2 its donor of model the formation of homo- and hetero-oligomers. data that binding of Bax to Bcl-2 on Bcl-2 but the of the to the monomeric Bcl-2 a for Bax the the Bcl-2 in this activated Bax of the for Bcl-2 been using a system and various Bcl-2 T. 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