4S0O

Crystal Structure of the Autoinhibited Dimer of Pro-apoptotic BAX (I)

Summary for 4S0O

• Entry DOI: 10.2210/pdb4s0o/pdb
• Related: 1F16 4S0P
• Descriptor: Apoptosis regulator BAX (2 entities in total)
• Functional Keywords: bcl-2 family protein, apoptosis regulator, autoinhibited dimer, apoptosis
• Biological source: Homo sapiens (human)
• Cellular location: Isoform Alpha: Mitochondrion membrane; Single-pass membrane protein. Isoform Beta: Cytoplasm. Isoform Gamma: Cytoplasm. Isoform Delta: Cytoplasm : Q07812
• Total number of polymer chains: 2
• Total formula weight: 42328.58

Authors

Priyadarshi, A.,Gavathiotis, E. (deposition date: 2015-01-02, release date: 2016-07-20, Last modification date: 2023-09-20)

Primary citation

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.
An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway.
Mol.Cell, 63:485-497, 2016

PubMed 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.

PubMed: 27425408
DOI: 10.1016/j.molcel.2016.06.010

Experimental method

X-RAY DIFFRACTION (1.9 Å)