An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway

Thomas P. Garner, Denis E. Reyna, Amit Priyadarshi, Hui Chen Chen, Sheng Li, Yang Wu, Yogesh Tengarai Ganesan, Vladimir N. Malashkevich, Steve S. Almo, Emily H. Cheng, Evripidis Gavathiotis

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23 Scopus citations

Abstract

Pro-apoptotic BAX is a cell fate regulator playing an important role in cellular homeostasis and pathological cell death. BAX is predominantly localized in the cytosol, where it has a quiescent monomer conformation. Following a pro-apoptotic trigger, cytosolic BAX is activated and translocates to the mitochondria to initiate mitochondrial dysfunction and apoptosis. Here, cellular, biochemical, and structural data unexpectedly demonstrate that cytosolic BAX also has an inactive dimer conformation that regulates its activation. The full-length crystal structure of the inactive BAX dimer revealed an asymmetric interaction consistent with inhibition of the N-terminal conformational change of one protomer and the displacement of the C-terminal helix α9 of the second protomer. This autoinhibited BAX dimer dissociates to BAX monomers before BAX can be activated. Our data support a model whereby the degree of apoptosis induction is regulated by the conformation of cytosolic BAX and identify an unprecedented mechanism of cytosolic BAX inhibition.

Original languageEnglish (US)
Pages (from-to)485-497
Number of pages13
JournalMolecular Cell
Volume63
Issue number3
DOIs
StatePublished - Aug 4 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Garner, T. P., Reyna, D. E., Priyadarshi, A., Chen, H. C., Li, S., Wu, Y., Ganesan, Y. T., Malashkevich, V. N., Almo, S. S., Cheng, E. H., & Gavathiotis, E. (2016). An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. Molecular Cell, 63(3), 485-497. https://doi.org/10.1016/j.molcel.2016.06.010