Journal article
Physiological restraint of Bak by Bcl-xL is essential for cell survival
EF Lee, S Grabow, S Chappaz, G Dewson, C Hockings, RM Kluck, MA Debrincat, DH Gray, MT Witkowski, M Evangelista, A Pettikiriarachchi, P Bouillet, RM Lane, PE Czabotar, PM Colman, BJ Smith, BT Kile, WD Fairlie
Genes and Development | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2016
Open access
Abstract
Due to the myriad interactions between prosurvival and proapoptotic members of the Bcl-2 family of proteins, establishing the mechanisms that regulate the intrinsic apoptotic pathway has proven challenging. Mechanistic insights have primarily been gleaned from in vitro studies because genetic approaches in mammals that produce unambiguous data are difficult to design. Here we describe a mutation in mouse and human Bak that specifically disrupts its interaction with the prosurvival protein Bcl-xL. Substitution of Glu75 in mBak (hBAK Q77) for leucine does not affect the three-dimensional structure of Bak or killing activity but reduces its affinity for Bcl-xL via loss of a single hydrogen bond..
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Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank Lorraine O'Reilly (Walter and Eliza Hall Institute) and Andreas Strasser (Walter and Eliza Hall Institute) for provision of some antibodies, and Sweta Iyer (Walter and Eliza Hall Institute) for technical assistance. This work was supported by Program Grants (1016701 and 1016647), Project Grants (1041936 and 575561), a Career Development Fellowship (1024620), and Fellowships (1022618, 1063008, 1042629, and 1079700) from the National Health and Medical Research Council of Australia; a Fellowship (FT100100791) from the Australian Research Council (ARC); a Cancer Council of Victoria Grant-in-Aid (1057949); and a Specialised Center of Research grant (7015) from the Leukemia and Lymphoma Society. S.G. was supported by Cancer Council of Victoria, Leukaemia Foundation Australia, the Lady Tata Memorial Trust, Melbourne International Research, the Melbourne International Fee Remission Scholarship (University of Melbourne), and Cancer Therapeutics CRC Top-up Scholarship. Infrastructure support was provided by National Health and Medical Research Council of Australia Independent Research Institute Infrastructure Support Scheme grant 361646 and a Victorian State Government Operational Infrastructure Program grant.