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, Steven C. Almo, Emily H. Cheng, Evripidis Gavathiotis

Research output: Contribution to journalArticle

20 Citations (Scopus)

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. Cytosolic BAX is thought to be a monomer that is activated by BH3-only proteins to induce cell death. Garner et al. show that cytosolic BAX can form a homo-dimer whose structure inhibits BAX activation, revealing a step in the regulation of BAX that modulates apoptosis.

Original languageEnglish (US)
JournalMolecular Cell
DOIs
StateAccepted/In press - Nov 23 2015

Fingerprint

Protein Subunits
Apoptosis
Cell Death
Cytosol
Mitochondria
Homeostasis
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. / Garner, Thomas P.; Reyna, Denis E.; Priyadarshi, Amit; Chen, Hui Chen; Li, Sheng; Wu, Yang; Ganesan, Yogesh Tengarai; Malashkevich, Vladimir N.; Almo, Steven C.; Cheng, Emily H.; Gavathiotis, Evripidis.

In: Molecular Cell, 23.11.2015.

Research output: Contribution to journalArticle

Garner, TP, Reyna, DE, Priyadarshi, A, Chen, HC, Li, S, Wu, Y, Ganesan, YT, Malashkevich, VN, Almo, SC, Cheng, EH & Gavathiotis, E 2015, 'An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway', Molecular Cell. https://doi.org/10.1016/j.molcel.2016.06.010
Garner, Thomas P. ; Reyna, Denis E. ; Priyadarshi, Amit ; Chen, Hui Chen ; Li, Sheng ; Wu, Yang ; Ganesan, Yogesh Tengarai ; Malashkevich, Vladimir N. ; Almo, Steven C. ; Cheng, Emily H. ; Gavathiotis, Evripidis. / An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway. In: Molecular Cell. 2015.
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