Journal article
Bak Core and Latch Domains Separate during Activation, and Freed Core Domains Form Symmetric Homodimers
J Brouwer, D Westphal, G Dewson, A Robin, R Uren, R Bartolo, G Thompson, P Colman, R Kluck, P Czabotar
Molecular Cell | Published : 2014
Abstract
Apoptotic stimuli activate and oligomerize the proapoptotic proteins Bak and Bax, resulting in mitochondrial outer-membrane permeabilization and subsequent cell death. This activation can occur when certain BH3-only proteins interact directly with Bak and Bax. Recently published crystal structures reveal that Bax separates into core and latch domains in response to BH3 peptides. The distinguishing characteristics of BH3 peptides capable of directly activating Bax were also elucidated. Here we identify specific BH3 peptides capable of "unlatching" Bak and describe structural insights into Bak activation and oligomerization. Crystal structures and crosslinking experiments demonstrate that Bak ..
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Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
We thank Ahmad Wardak and Callum Lawrence for technical support, beamline staff at the Australian Synchrotron where diffraction data were collected, and Masato Kawasaki for the pET28a-GFP vector. Crystallization experiments were performed at the Bio21 C3 Collaborative Crystallization Centre. P. E. C., G. D., and R. M. K. acknowledge ARC Future Fellowships; J.M.B. acknowledges an Australian Postgraduate Award; and P. M. C. acknowledges an NHMRC Fellowship. Our work is supported by NHMRC (Australia; Projects Grants 1059331 and 1023055 and Program Grant 1016701), the Australian Cancer Research Foundation, the Leukemia and Lymphoma Society (US), the Victorian State Government Operational Infrastructure Support, and the Australian Government NHMRC IRIISS.