Institut de Biochimie et de Génétique Cellulaire, CNRS, Université de Bordeaux
The membrane insertion of the pro- apoptotic protein Bax is a Tom22-dependent multi-step process: a study in nanodiscs.
Cell Death Discov. 2024 Jul 23;10(1):335. doi: 10.1038/s41420-024-02108-x. PMID: 39043635; PMCID: PMC11266675.
Rouchidane Eyitayo A, Daury L, Priault M, Manon S.
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Akandé Rouchidane Eyitayo is a 32-year-old Doctor of Biochemistry. He obtained his Bachelor's degree in Biochemistry from the University of Science and Technology of Masuku (Franceville, Gabon) in 2017. In 2018, he was awarded a France-Gabon Cooperation Scholarship to study for a Master's degree in Biochemistry, Cellular and Molecular Biology at the University of Bordeaux. He did his Master 1 and 2 internship in the PRIMA team at the IBGC (Institute of Biochemistry and Cell Genetics, UMR5095, CNRS, University of Bordeaux) under the supervision of Dr Cécile Gonzalez and then Dr Stéphen Manon. In 2020, he obtained a grant from the Agence Nationale des Bourses du Gabon (ANBG) to carry out his PhD project entitled "The membrane insertion of the pro-apoptotic protein Bax is a multi-step TOM22-dependent process" under the supervision of Dr Stéphen Manon. He defended his thesis in December 2023. Dr Akandé Rouchidane is a specialist in the study of membrane proteins, with more specific knowledge of proteins in the Bcl-2 family. He is interested in the molecular mechanisms leading to the activation or repression of the pro- apoptotic activity of the Bax protein. He is currently a post-doctoral researcher in Prof. Bertrand Mollereau's team (ENS Lyon).
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Résumé de l'article
Membrane insertion of the pro-apoptotic protein Bax was investigated by setting up cell-free synthesis of full-length Bax in the presence of pre-formed nanodiscs. While Bax was spontaneously poorly inserted in nanodiscs, co-synthesis with the mitochondrial receptor Tom22 stimulated Bax membrane insertion. The initial interaction of Bax with the lipid bilayer exposed the hydrophobic GALLL motif in Hα1 leading to Bax precipitation through hydrophobic interactions. The same motif was recognized by Tom22, triggering conformational changes leading to the extrusion and the ensuing membrane insertion of the C-terminal hydrophobic Hα9. Tom22 was also required for Bax-membrane insertion after Bax was activated either by BH3-activators or by its release from Bcl-xL by WEHI-539. The effect of Tom22 was impaired by D154Y substitution in Bax-Hα7 and T174P substitution in Bax-Hα9, which are found in several tumors. Conversely, a R9E substitution promoted a spontaneous insertion of Bax in nanodiscs, in the absence of Tom22. Both Tom22-activated Bax and BaxR9E alone permeabilized liposomes to dextran-10kDa and formed ~5-nm-diameter pores in nanodiscs. The concerted regulation of Bax membrane insertion by Tom22 and BH3-activators is discussed.
