Journal article
Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis
PE Czabotar, D Westphal, G Dewson, S Ma, C Hockings, WD Fairlie, EF Lee, S Yao, AY Robin, BJ Smith, DCS Huang, RM Kluck, JM Adams, PM Colman
Cell | CELL PRESS | Published : 2013
Abstract
In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. F..
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Funding Acknowledgements
We thank Ahmed Wardak, Geoff Thompson, Hong Yang, Eden Whitlock, and Leonie Gibson for technical support; Jacqui Gulbis for comments on the manuscript; and beamline staff at the Australian Synchrotron, where diffraction data were collected. We thank Richard Youle for the full-length Bax construct, Motoshi Suzuki and Nico Tjandra for NMR chemical shift data, and Masato Kawasaki for the pET28a-GFP vector. Crystallization experiments were performed at the Bio21 C3 Collaborative Crystallization Centre. P.E.C. acknowledges an ARC Future Fellowship, and D.W. acknowledges a DFG (Germany) Postdoctoral Fellowship. Our work is supported by NHMRC (Australia), ARC (Australia), the Australian Cancer Research Foundation, the Cancer Council of Victoria, the Leukemia and Lymphoma Society (US), the Victorian State Government Operational Infrastructure Support, and the Australian Government NHMRC IRIISS.