Structure of detergent-activated BAK dimers derived from the inert monomer

• Published in: Molecular cell 2021-05, Vol.81 (10), p.2123-2134.e5
• Main Authors: Birkinshaw, Richard W., Iyer, Sweta, Lio, Daisy, Luo, Cindy S., Brouwer, Jason M., Miller, Michelle S., Robin, Adeline Y., Uren, Rachel T., Dewson, Grant, Kluck, Ruth M., Colman, Peter M., Czabotar, Peter E.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis; BAK; BAK activation; BCL-2 family proteins; bcl-2 Homologous Antagonist-Killer Protein - chemistry; bcl-2 Homologous Antagonist-Killer Protein - metabolism; BH3-in-groove core dimers; cytochrome c release; Detergent mediated dimerization; Detergents - chemistry; Liposomes; membrane rupture; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Protein Multimerization; Protein Structure, Secondary; X-ray crystallography
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.03.014

A body of data supports the existence of core (α2–α5) dimers of BAK and BAX in the oligomeric, membrane-perturbing conformation of these essential apoptotic effector molecules. Molecular structures for these dimers have only been captured for truncated constructs encompassing the core domain alone. Here, we report a crystal structure of BAK α2–α8 dimers (i.e., minus its flexible N-terminal helix and membrane-anchoring C-terminal segment) that has been obtained through the activation of monomeric BAK with the detergent C12E8. Core dimers are evident, linked through the crystal by contacts via latch (α6–α8) domains. This crystal structure shows activated BAK dimers with the extended latch domain present. Our data provide direct evidence for the conformational change converting BAK from inert monomer to the functional dimer that destroys mitochondrial integrity. This dimer is the smallest functional unit for recombinant BAK or BAX described so far. [Display omitted] •BAK monomers are activated by C12E8 detergent to form activated dimers•The crystal structure of these activated BAK dimers is described•The structure provides direct evidence for BAK conformational changes on activation•The active dimer has an extended hydrophobic surface that disrupts lipid membranes BAK inert monomers convert to activated membrane-rupturing dimers during apoptosis. Birkinshaw et al. describe the activation of BAK monomers into dimers that rupture lipid membranes and release cytochrome c from mitochondria. They describe the crystal structure of functional BAK dimers, confirming the conformational changes required for an active complex.