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Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis

journal contribution
posted on 06.11.2020, 02:40 by N Popgeorgiev, JD Sa, L Jabbour, Suresh Banjara, TTM Nguyen, A Akhavan-E-Sabet, R Gadet, N Ralchev, S Manon, MG Hinds, HJ Osigus, B Schierwater, Patrick Humbert, R Rimokh, G Gillet, Marc Kvansakul
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). In metazoans, Bcl-2 family proteins are major regulators of mitochondrially mediated apoptosis; however, their evolution remains poorly understood. Here, we describe the molecular characterization of the four members of the Bcl-2 family in the most primitive metazoan, Trichoplax adhaerens All four trBcl-2 homologs are multimotif Bcl-2 group, with trBcl-2L1 and trBcl-2L2 being highly divergent antiapoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 are homologs of proapoptotic Bax and Bak, respectively. trBax expression permeabilizes the mitochondrial outer membrane, while trBak operates as a BH3-only sensitizer repressing antiapoptotic activities of trBcl-2L1 and trBcl-2L2. The crystal structure of a trBcl-2L2:trBak BH3 complex reveals that trBcl-2L2 uses the canonical Bcl-2 ligand binding groove to sequester trBak BH3, indicating that the structural basis for apoptosis control is conserved from T. adhaerens to mammals. Finally, we demonstrate that both trBax and trBak BH3 peptides bind selectively to human Bcl-2 homologs to sensitize cancer cells to chemotherapy treatment.

Funding

This research was supported by Ligue nationale contre le cancer (Comite du Rhone) (to N.P.), Fondation ARC (grant no. PGA1 RF20180206799 to G.G.), France BioImaging infrastructure ANR-10-INBS-04, Morphoscope ANR-11-EQPX-0029, and InterDIM 2011 Region Paris Ile-de-France and the Australian Research Council (DP190103591 to M.K.).

Ligue nationale contre le cancer (Comite du Rhone)

Fondation ARC | PGA1 RF20180206799

France BioImaging infrastructure | ANR-10-INBS-04

France BioImaging Morphoscope | ANR-11-EQPX-0029

InterDIM 2011 Region Paris Ile-de-France

Australian Research Council | DP190103591

History

Publication Date

01/01/2020

Journal

Science Advances

Volume

6

Issue

40

Article Number

eabc4149

Pagination

13p. (p. 1-13)

Publisher

American Association for the Advancement of Science

ISSN

2375-2548

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

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