A novel lipid-binding hydrophobic funnel within BAX promotes the mitochondrial pathway of apoptosis
Jesse D. Gelles1,2,5, Mark P. A. Luna-Vargas1,2, Tara M. Sebastian1,2,5, Jarvier N. Mohammed1, Arie Zask6,7, Brent R. Stockwell6,7 and Jerry E. Chipuk1,2,3,4,5* 1Department of Oncological Sciences, 2Tisch Cancer Institute, 3Diabetes, Obesity, and Metabolism Institute, 4Department of Dermatology, 5Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1130, New York, New York 10029 USA; 6Department of Chemistry, 7Department of Biological Sciences, Columbia University, New York, New York 10027 USA *Corresponding author: firstname.lastname@example.org
Mitochondrial outer membrane permeabilization (MOMP) is a critical signal in apoptosis and depends upon protein-protein and protein-lipid interactions. While mitochondrial lipid composition effects and affects BAX-dependent MOMP, molecular mechanisms remain unknown. Using integrated structural approaches, we define and characterize a hydrophobic funnel within BAX comprised of alpha helices 1, 5, 6, and 8. This hydrophobic funnel is unique to BAX, and cooperates with a lipidic cofactor (trans-2-hexadecenal) to promote BAX conformational changes associated with activation. Furthermore, we employ complementary biochemical, biophysical, and cellular techniques to mechanistically interrogate the BAX:trans-2-hexadecenal interaction. Collectively, this work redefines the fundamental mechanisms of BAX activation, MOMP, and the cellular commitment to apoptosis.
Credits: None available.
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