6eb6
From Proteopedia
Crystal structure of BAX W139A monomer
Structural highlights
FunctionBAX_HUMAN Accelerates programmed cell death by binding to, and antagonizing the apoptosis repressor BCL2 or its adenovirus homolog E1B 19k protein. Under stress conditions, undergoes a conformation change that causes translocation to the mitochondrion membrane, leading to the release of cytochrome c that then triggers apoptosis. Promotes activation of CASP3, and thereby apoptosis.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedTo elicit apoptosis, BAX metamorphoses from an inert cytosolic monomer into homo-oligomers that permeabilize the mitochondrial outer membrane (MOM). A long-standing puzzle is that BH3 domains apparently activate BAX by not only its canonical groove but also a proposed site involving helices alpha1 and alpha6. Our mutagenesis studies reveal that late steps like oligomerization require activation through the groove but probably not earlier steps like MOM association. Conversely, alpha1 or alpha6 obstruction and alanine mutagenesis scanning implicate these helices early in BAX activation. The alpha1 and alpha6 mutations lowered BH3 binding, altered the BAX conformation, and reduced its MOM translocation and integration; their exposure of the BAX alpha1-alpha2 loop allosterically sequestered its alpha9 membrane anchor in the groove. The crystal structure of an alpha6 mutant revealed additional allosteric effects. The results suggest that the alpha1 and alpha6 region drives MOM association and integration, whereas groove binding favors subsequent steps toward oligomerization. BAX Activation: Mutations Near Its Proposed Non-canonical BH3 Binding Site Reveal Allosteric Changes Controlling Mitochondrial Association.,Dengler MA, Robin AY, Gibson L, Li MX, Sandow JJ, Iyer S, Webb AI, Westphal D, Dewson G, Adams JM Cell Rep. 2019 Apr 9;27(2):359-373.e6. doi: 10.1016/j.celrep.2019.03.040. PMID:30970242[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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