BAX mitochondrial integration is regulated allosterically by its α1-α2 loop
- Author(s)
- Dengler, MA; Gibson, L; Adams, JM;
- Details
- Publication Year 2021-06-16,Volume 28,Issue #12,Page 3270-3281
- Journal Title
- Cell Death and Differentiation
- Abstract
- The conformational changes converting BAX from an inert cytosolic monomer into the homo-oligomers that permeabilize the mitochondrial outer membrane (MOM) are crucial steps toward apoptosis. Here, we have explored the potential role of the BAX α1-α2 loop in this process by three mutagenic approaches: replacing loop segments with cognate loop regions from closely related proteins, alanine scanning and analysis of BAX α1-α2 loop missense mutations observed in tumours. Responsiveness to a death signal, such as tBID, was reduced by mutations in the N-terminal but not C-terminal half of the loop. N-terminal loop variants, which were enriched in tumours, impaired MOM integration by allosterically reducing exposure of the BAX α9 transmembrane anchor. Most C-terminal loop variants reduced BAX stability, leading to increased BAX apoptotic function in some variants. Thus, our systematic mutagenesis suggests that the two halves of the α1-α2 loop have distinct functions. We show that the N-terminal half of the loop (its first nine residues) comprises an important allosteric regulator of BAX activation by setting the proportion of MOM-integrated BAX following a death signal. The enrichment of N-terminal loop mutations in tumours indicates that they may promote tumour cell survival and underscore the loop as a target for therapeutic manipulation of BAX function.
- Publisher
- NPG
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 34135480
- Publisher's Version
- https://doi.org/10.1038/s41418-021-00815-x
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-06-21 10:25:55
Last Modified: 2021-12-07 11:54:34