Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane

作者：Westphal Dana; Dewson Grant; Menard Marie; Frederick Paul; Iyer Sweta; Bartolo Ray; Gibson Leonie; Czabotar Peter E; Smith Brian J; Adams Jerry M^*; Kluck Ruth M

来源：Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(39): E4076-E4085.

DOI：10.1073/pnas.1415142111

• cell death
• mitochondrial permeabilization
• protein-membrane topology
• membrane pores
• cysteine-scanning mutagenesis

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 alpha-helices, alpha 5 and alpha 6, 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 alpha 5 (like Bax alpha 5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in alpha 5 and alpha 6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which alpha 5 and alpha 6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.

• 出版日期2014-9-30
• 单位河北医科大学