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

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posted on 2023-03-09, 00:11 authored by S Iyer, K Anwari, AE Alsop, WS Yuen, DCS Huang, J Carroll, Nicholas SmithNicholas Smith, Brian SmithBrian Smith, G Dewson, RM Kluck
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.


Supported by grants from the National Health and Medical Research Council of Australia (no. 637337, no. 1008434 and no. 1016701), Australian Research Council Future Fellowships (R.M.K. and G.D.), operational infrastructure grants through the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS, and computational resources from the Victorian Life Sciences Computation Initiative (VLSCI).


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Nature Communications



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Nature Publishing Group



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