title: Crystal structure of Bax bound to the BH3 peptide of Bim identifies important contacts for interaction.
abstract: The BH3-only protein Bim is a potent direct activator of the proapoptotic effector protein Bax, but the structural basis for its activity has remained poorly defined. Here we describe the crystal structure of the BimBH3 peptide bound to BaxΔC26 and structure-based mutagenesis studies. Similar to BidBH3, the BimBH3 peptide binds into the cognate surface groove of Bax using the conserved hydrophobic BH3 residues h1-h4. However, the structure and mutagenesis data show that Bim is less reliant compared with Bid on its 'h0' residues for activating Bax and that a single amino-acid difference between Bim and Bid encodes a fivefold difference in Bax-binding potency. Similar to the structures of BidBH3 and BaxBH3 bound to BaxΔC21, the structure of the BimBH3 complex with BaxΔC displays a cavity surrounded by Bax α1, α2, α5 and α8. Our results are consistent with a model in which binding of an activator BH3 domain to the Bax groove initiates separation of its core (α2-α5) and latch (α6-α8) domains, enabling its subsequent dimerisation and the permeabilisation of the mitochondrial outer membrane.
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: A Y
authors.initials: AY
authors.lastname: Robin
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Krishna Kumar
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Westphal
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Wardak
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors.forename: G V
authors.initials: GV
authors.lastname: Thompson
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Dewson
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Colman
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: P E
authors.initials: PE
authors.lastname: Czabotar
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D016296:Mutagenesis; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C474007:Bax protein (53-86); D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein