title: Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices.
abstract: A pivotal step toward apoptosis is oligomerization of the Bcl-2 relative Bak. We recently reported that its oligomerization initiates by insertion of an exposed BH3 domain into the groove of another Bak monomer. We now report that the resulting BH3:groove dimers can be converted to the larger oligomers that permeabilize mitochondria by an interface between alpha6 helices. Cysteine residues placed in alpha6 could be crosslinked only after apoptotic signaling. Cysteines placed at both interfaces established that the BH3:groove dimer is symmetric and that the alpha6:alpha6 interface can link these dimers into homo-oligomers containing at least 18 Bak molecules. A putative zinc-binding site in alpha6 was not required to form the alpha6:alpha6 interface, and its mutation in full-length Bak did not affect Bak conformation, oligomerization, or function. We conclude that alpha6:alpha6 interaction occurs during Bak oligomerization and proapoptotic function, but we find no evidence that zinc binding to that interface regulates apoptosis.
authors: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Parkville Victoria, Australia.
authors: Grant
authors: G
authors: Dewson
authors: Tobias
authors: T
authors: Kratina
authors: Peter
authors: P
authors: Czabotar
authors: Catherine L
authors: CL
authors: Day
authors: Jerry M
authors: JM
authors: Adams
authors: Ruth M
authors: RM
authors: Kluck
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D045304:Cytochromes c / Q000378:metabolism; D051379:Mice; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D050998:bcl-2 Homologous Antagonist-Killer Protein; D045304:Cytochromes c; D015032:Zinc