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.; Cheng, Emily H.; Gavathiotis, Evripidis

doi:10.1016/j.molcel.2016.06.010

An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway

Journal Article · Thu Jul 14 00:00:00 EDT 2016 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2016.06.010· OSTI ID:1351350

Garner, Thomas P. ^[1]; Reyna, Denis E. ^[1]; Priyadarshi, Amit ^[1]; Chen, Hui-Chen ^[2]; Li, Sheng ^[3]; Wu, Yang ^[1]; Ganesan, Yogesh Tengarai ^[2]; Malashkevich, Vladimir N. ^[1]; Cheng, Emily H. ^[2]; Gavathiotis, Evripidis ^[1]

Albert Einstein College of Medicine, Bronx, NY (United States)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)
Univ. of California, San Diego, La Jolla, CA (United States)

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. Furthermore, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1351350

Journal Information:: Molecular Cell, Journal Name: Molecular Cell Journal Issue: 3 Vol. 63; ISSN 1097-2765

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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