Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
| Autor: | Grant Dewson, Brian J. Smith, Leonie Gibson, Paul Frederick, Sweta Iyer, D. Westphal, Marie Menard, Jerry M. Adams, Ray Bartolo, Ruth M. Kluck, Peter E. Czabotar |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Programmed cell death Molecular Sequence Data Perforation (oil well) Apoptosis Biology Protein Structure Secondary Cell Line Mice Protein structure Bcl-2-associated X protein Stilbenes Animals Humans Amino Acid Sequence Cysteine Protein Structure Quaternary Peptide sequence bcl-2-Associated X Protein Multidisciplinary Sulfhydryl Reagents Bcl-2 family Molecular biology Recombinant Proteins Protein Structure Tertiary bcl-2 Homologous Antagonist-Killer Protein Amino Acid Substitution PNAS Plus Mitochondrial Membranes Mutagenesis Site-Directed Biophysics biology.protein biological phenomena cell phenomena and immunity Bacterial outer membrane Bcl-2 Homologous Antagonist-Killer Protein |
| Zdroj: | Proceedings of the National Academy of Sciences. 111 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | The pivotal step on the mitochondrial pathway to apoptosis is permeabilization of the mitochondrial outer membrane (MOM) by oligomers of the B-cell lymphoma-2 (Bcl-2) family members Bak or Bax. However, how they disrupt MOM integrity is unknown. A longstanding model is that activated Bak and Bax insert two α-helices, α5 and α6, as a hairpin across the MOM, but recent insights on the oligomer structures question this model. We have clarified how these helices contribute to MOM perforation by determining that, in the oligomers, Bak α5 (like Bax α5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in α5 and α6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which α5 and α6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores. |
| Databáze: | OpenAIRE |
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