How does BAX become a cell killer?

Seminar/Forum

How does BAX become a cell killer?

Davis Auditorium
Walter and Eliza Hall Institute

Parkville

1g Royal Parade

Booking not required

Further Details

T: (03) 9345 2555

reception@wehi.edu.au

https://www.wehi.edu.au

BAX and BAK share the crucial role of driving apoptosis by perforating the mitochondrial outer membrane (MOM), releasing factors such as cytochrome c that help activate the caspases that dismantle the cell. Their locations in healthy cells differ: whereas BAK is almost entirely integrated into the MOM, which its C-terminal MOM-targeting helix spans, BAX is mostly cytosolic, with its C-terminal helix held in a canonical surface groove similar to that on BAK and pro-survival relatives. Apoptotic signals, mediated by BH3-only proteins like BIM or BID, evoke radical conformational changes that drive BAX to the MOM and convert BAX and BAK into MOM-permeabilizing oligomers. These ‘activators’ can engage both BAX and BAK by inserting their BH3 association domain into the canonical surface groove, but since that of cytosolic BAX is occluded, they have been proposed to bind instead to an incompletely defined BAX ‘rear site’.

In a remarkable metamorphosis, triggered BAX or BAK unfolds into three segments, and the ‘core’ (alpha helices 2-5) forms a ‘symmetric dimer’ with another such molecule by inserting the BH3 domain (helix 2) of one molecule into the groove (helices 3-5) of the other, and vice versa. These novel dimers are the central unit of the larger oligomers, but how the dimers couple into oligomers and disrupt the MOM remain largely a mystery.

Professor Adams will address how BAX activation is triggered (Michael Dingler’s work), and discuss initial efforts to apply cryo-EM to examine BAX oligomers (Bin Wang’s work).

Review reference: Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014 Jan;15(1):49-63.

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