Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies
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
WEHI Research Division(s)
Molecular Genetics Of Cancer; Cancer And Haematology; Cell Signalling And Cell Death
PubMed ID
27217060
NHMRC Grants
NHMRC/637337 NHMRC/1008434 NHMRC/1016701
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
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