Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis
| Autor: | Popgeorgiev, Nikolay, Sa, Jaison D, Jabbour, Lea, Banjara, Suresh, Nguyen, Trang Thi Minh, Akhavan-E-Sabet, Aida, Gadet, Rudy, Ralchev, Nikola, Manon, Stéphen, Hinds, Mark G., Osigus, Hans-Jürgen, Schierwater, Bernd, Humbert, Patrick O., Rimokh, Ruth, Gillet, Germain, Kvansakul, Marc |
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| Přispěvatelé: | manon, stéphen, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mammals
Evolutionary Biology SciAdv r-articles Apoptosis [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] Mitochondria bcl-2 Homologous Antagonist-Killer Protein Structural Biology Mitochondrial Membranes [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] Animals Humans biological phenomena cell phenomena and immunity [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Research Articles Research Article |
| Zdroj: | Science Advances Science Advances, 2020 Science Advances, American Association for the Advancement of Science (AAAS), 2020 |
| ISSN: | 2375-2548 |
| Popis: | Bcl-2 proteins are molecular gatekeepers of the mitochondrial pathway of apoptosis that emerged early during metazoan evolution. 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. |
| Databáze: | OpenAIRE |
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