Allosteric Regulation of BH3 Proteins in Bcl-xL Complexes Enables Switch-like Activation of Bax

Christian Bogner; Justin Kale; Justin Pogmore; Xiaoke Chi; Aisha Shamas-Din; Cécile Fradin; Brian Leber; David W Andrews

doi:10.1016/j.molcel.2019.12.025

Allosteric Regulation of BH3 Proteins in Bcl-x_L Complexes Enables Switch-like Activation of Bax

Mol Cell. 2020 Feb 20;77(4):901-912.e9. doi: 10.1016/j.molcel.2019.12.025. Epub 2020 Jan 27.

Authors

Christian Bogner¹, Justin Kale², Justin Pogmore², Xiaoke Chi², Aisha Shamas-Din³, Cécile Fradin⁴, Brian Leber⁵, David W Andrews⁶

Affiliations

¹ Sunnybrook Research Institute, University of Toronto, Toronto, ON M5S 1A1, Canada; Third Department of Medicine, Klinikum Rechts der Isar, Technische Universität München, München 80333, Germany.
² Sunnybrook Research Institute, University of Toronto, Toronto, ON M5S 1A1, Canada.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
⁴ Departments of Biomedical Sciences and Biochemistry, McMaster University, Hamilton, ON L8S 4L8, Canada; Departments of Physics and Astronomy, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Departments of Biomedical Sciences and Biochemistry, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁶ Sunnybrook Research Institute, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A1, Canada; Departments of Biomedical Sciences and Biochemistry, McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address: david.andrews@sri.utoronto.ca.

PMID: 32001105
DOI: 10.1016/j.molcel.2019.12.025

Abstract

Current models of apoptosis regulation by the Bcl-2 family of proteins postulate that heterodimeric interactions between family members determine whether Bax and Bak are activated to trigger cell death. Thus, the relative abundance and binding affinities between pro- and anti-apoptotic proteins determines the outcome of these interactions. Examination of these interactions using purified mitochondria and liposomes with full-length recombinant proteins revealed that Bcl-x_L inhibits apoptosis as a higher-order complex that binds multiple BH3 proteins. Allosteric regulation of this complex by the BH3 sensitizer Bad confers switch-like activity to the indirect activation of Bax. The BH3 activator cBid sequestered by Bcl-x_L complexes changes from an inactive to an active form while bound to a Bcl-x_L complex only when Bad is also bound. Bcl-x_L complexes enable Bad to function as a non-competitive inhibitor of Bcl-x_L and allosterically activate cBid, dramatically enhancing the pro-apoptotic potency of Bad.

Keywords: Bad; Bax; Bcl-2 family; Bcl-xL complexes; Bid; MOMP; allosteric activation; apoptosis; mitochondria; switch-like activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Animals
Apoptosis
BH3 Interacting Domain Death Agonist Protein / metabolism
Cell Line
Humans
Mice
Mitochondrial Membranes / metabolism
bcl-2-Associated X Protein / metabolism*
bcl-Associated Death Protein / metabolism
bcl-X Protein / chemistry
bcl-X Protein / metabolism*

Substances

BH3 Interacting Domain Death Agonist Protein
bcl-2-Associated X Protein
bcl-Associated Death Protein
bcl-X Protein

Grants and funding

FDN143312 /CIHR/Canada