Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies

Sweta Iyer, Khatira Anwari, Amber E. Alsop, Wai Shan Yuen, David C. S. Huang, John Carroll, Nicholas A. Smith, Brian J. Smith, Grant Dewson, Ruth M. Kluck

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


During apoptosis, Bak and Bax are activated by BH3-only proteins binding to the alpha 2-alpha 5 hydrophobic groove; Bax is also activated via a rear pocket. Here we report that antibodies can directly activate Bak and mitochondrial Bax by binding to the alpha 1-alpha 2 loop. A monoclonal antibody (clone 7D10) binds close to alpha 1 in non-activated Bak to induce conformational change, oligomerization, and cytochrome c release. Anti-FLAG antibodies also activate Bak containing a FLAG epitope close to alpha 1. An antibody (clone 3C10) to the Bax alpha 1-alpha 2 loop activates mitochondrial Bax, but blocks translocation of cytosolic Bax. Tethers within Bak show that 7D10 binding directly extricates alpha 1; a structural model of the 7D10 Fab bound to Bak reveals the formation of a cavity under alpha 1. Our identification of the alpha 1-alpha 2 loop as an activation site in Bak paves the way to develop intrabodies or small molecules that directly and selectively regulate these proteins.

Original languageEnglish
Article number11734
Number of pages10
JournalNature Communications
Publication statusPublished - 24 May 2016
Externally publishedYes


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