Journal article

BAK core dimers bind lipids and can be bridged by them

Angus D Cowan, Nicholas A Smith, Jarrod J Sandow, Eugene A Kapp, Yepy H Rustam, James M Murphy, Jason M Brouwer, Jonathan P Bernardini, Michael J Roy, Ahmad Z Wardak, Iris K Tan, Andrew I Webb, Jacqueline M Gulbis, Brian J Smith, Gavin E Reid, Grant Dewson, Peter M Colman, Peter E Czabotar



BAK and BAX are essential mediators of apoptosis that oligomerize in response to death cues, thereby causing permeabilization of the mitochondrial outer membrane. Their transition from quiescent monomers to pore-forming oligomers involves a well-characterized symmetric dimer intermediate. However, no essential secondary interface that can be disrupted by mutagenesis has been identified. Here we describe crystal structures of human BAK core domain (α2-α5) dimers that reveal preferred binding sites for membrane lipids and detergents. The phospholipid headgroup and one acyl chain (sn2) associate with one core dimer while the other acyl chain (sn1) associates with a neighboring core dimer, sugge..

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Awarded by NHMRC

Awarded by ARC

Awarded by Leukemia and Lymphoma Society (US) (SCOR grant)

Awarded by Australian Government NHMRC IRIISS

Awarded by Intersect Australia under LIEF grant

Awarded by LIEF Grant

Funding Acknowledgements

We thank R. Kluck, G. Lessene, A. Robin, R. Birkinshaw, C. Robinson and K. Gupta for discussions and comments on the manuscript and Z. Liu for assistance with mitochondrial experiments. This research was undertaken in part using the MX1 and MX2 crystallography and SAXS-WAXS beamlines at the Australian Synchrotron and made use of the ACRF Detector. We thank the staff at this facility for assistance with data collection and the staff at the Collaborative Crystallisation Centre for assistance with crystallization experiments. We acknowledge an Australian Postgraduate Award for A.D.C. and NHMRC fellowships to P.E.C., P.M.C. and J.M.M. (1079700, 1116934 and 1172929). Our work is supported by the NHMRC (project grants 1079706 and 1059290 and program grant 1113133), the ARC (Linkage Infrastructure, Equipment and Facilities Grant LE160100015), the Australian Cancer Research Foundation, the Leukemia and Lymphoma Society (US) (SCOR grant 7001-03), the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS (9000587). Part of this work was undertaken using resources from the National Computational Infrastructure, which is supported by the Australian government and provided through Intersect Australia under LIEF grant LE170100032 and through the HPC-GPGPU Facility, which was established with the assistance of LIEF Grant LE170100200.