Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/123571
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Type: Journal article
Title: Physiological restraint of Bak by Bcl-x⌊ is essential for cell survival
Author: Lee, E.
Grabow, S.
Chappaz, S.
Dewson, G.
Hockings, C.
Kluck, R.
Debrincat, M.
Gray, D.
Witkowski, M.
Evangelista, M.
Pettikiriarachchi, A.
Bouillet, P.
Lane, R.
Czabotar, P.
Colman, P.
Smith, B.
Kile, B.
Fairlie, W.
Citation: Genes and Development, 2016; 30(10):1240-1250
Publisher: CSHL Press
Issue Date: 2016
ISSN: 0890-9369
1549-5477
Statement of
Responsibility: 
Erinna F. Lee, Stephanie Grabow, Stephane Chappaz, Grant Dewson, Colin Hockings ... Benjamin T. Kile ... et al.
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. Using this mutant, we investigated the requirement for physical restraint of Bak by Bcl-xL in apoptotic regulation. In vitro, Bak(Q75L) cells were significantly more sensitive to various apoptotic stimuli. In vivo, loss of Bcl-xL binding to Bak led to significant defects in T-cell and blood platelet survival. Thus, we provide the first definitive in vivo evidence that prosurvival proteins maintain cellular viability by interacting with and inhibiting Bak.
Keywords: Apoptosis; Bcl-2; BH3; Bak; Bcl-xL
Rights: © 2016 Lee et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution- NonCommercial 4.0 International), as described at http:// creativecommons.org/licenses/by-nc/4.0/.
RMID: 1000001831
DOI: 10.1101/gad.279414.116
Grant ID: http://purl.org/au-research/grants/nhmrc/1016701
http://purl.org/au-research/grants/nhmrc/1016647
http://purl.org/au-research/grants/nhmrc/1041936
http://purl.org/au-research/grants/nhmrc/575561
http://purl.org/au-research/grants/nhmrc/1024620
http://purl.org/au-research/grants/nhmrc/1022618
http://purl.org/au-research/grants/nhmrc/1063008
http://purl.org/au-research/grants/nhmrc/1042629
http://purl.org/au-research/grants/nhmrc/1079700
http://purl.org/au-research/grants/nhmrc/361646
http://purl.org/au-research/grants/arc/FT100100791
Appears in Collections:Medicine publications

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