Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Accéder directement au contenu
Article Dans Une Revue Science Advances Année : 2020

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

Jaison Sa
Suresh Banjara
Aida Akhavan-E-Sabet
  • Fonction : Auteur
Rudy Gadet
Mark Hinds
Hans-Jürgen Osigus
  • Fonction : Auteur
Bernd Schierwater
  • Fonction : Auteur
Patrick Humbert
Marc Kvansakul

Résumé

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.
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hal-03846699 , version 1 (12-02-2024)

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Nikolay Popgeorgiev, Jaison Sa, Lea Jabbour, Suresh Banjara, Trang Thi Minh Nguyen, et al.. Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis. Science Advances , 2020, 6 (40), pp.eabc4149. ⟨10.1126/sciadv.abc4149⟩. ⟨hal-03846699⟩
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