Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies
- Author(s)
- Iyer, S; Anwari, K; Alsop, AE; Yuen, WS; Huang, DC; Carroll, J; Smith, NA; Smith, BJ; Dewson, G; Kluck, RM;
- Journal Title
- Nat Commun
- Publication Type
- Journal Article
- Abstract
- During apoptosis, Bak and Bax are activated by BH3-only proteins binding to the alpha2-alpha5 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 alpha1-alpha2 loop. A monoclonal antibody (clone 7D10) binds close to alpha1 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 alpha1. An antibody (clone 3C10) to the Bax alpha1-alpha2 loop activates mitochondrial Bax, but blocks translocation of cytosolic Bax. Tethers within Bak show that 7D10 binding directly extricates alpha1; a structural model of the 7D10 Fab bound to Bak reveals the formation of a cavity under alpha1. Our identification of the alpha1-alpha2 loop as an activation site in Bak paves the way to develop intrabodies or small molecules that directly and selectively regulate these proteins.
- Publisher
- NPG
- Research Division(s)
- Molecular Genetics Of Cancer; Cancer And Haematology; Cell Signalling And Cell Death
- PubMed ID
- 27217060
- Publisher's Version
- https://doi.org/10.1038/ncomms11734
- Open Access at Publisher's Site
http://www.nature.com/ncomms/2016/160524/ncomms11734/full/ncomms11734.html- NHMRC Grants
- NHMRC/637337, NHMRC/1008434, NHMRC/1016701,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-06-16 10:27:05
Last Modified: 2016-06-16 11:31:15