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

Abstract:

:During apoptosis, Bak and Bax are activated by BH3-only proteins binding to the α2-α5 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 α1-α2 loop. A monoclonal antibody (clone 7D10) binds close to α1 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 α1. An antibody (clone 3C10) to the Bax α1-α2 loop activates mitochondrial Bax, but blocks translocation of cytosolic Bax. Tethers within Bak show that 7D10 binding directly extricates α1; a structural model of the 7D10 Fab bound to Bak reveals the formation of a cavity under α1. Our identification of the α1-α2 loop as an activation site in Bak paves the way to develop intrabodies or small molecules that directly and selectively regulate these proteins.

journal_name

Nat Commun

journal_title

Nature communications

authors

Iyer S,Anwari K,Alsop AE,Yuen WS,Huang DC,Carroll J,Smith NA,Smith BJ,Dewson G,Kluck RM

doi

10.1038/ncomms11734

subject

Has Abstract

pub_date

2016-05-24 00:00:00

pages

11734

issn

2041-1723

pii

ncomms11734

journal_volume

7

pub_type

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