Membrane Binding and Dimerization of Bax Protein are Coupled to a Series of Conformational Changes

Abstract

Proteins of the Bcl-2 family are important regulators of apoptosis, and contributors of various diseases. Pro-apoptotic Bax proteins activated by BH3-only proteins translocate from the cytosol to the mitochondria, forming oligomers to permeabilize the mitochondrial outer membrane and initiate apoptosis. The underlying molecular mechanisms remain unclear. In this study we assayed Bax interactions with each other and with a model mitochondrial membrane. The results show that dimerization of Bax proteins in cytosol facilitates the membrane binding. Interaction with a peptide containing the BH3 region of Bax enhances both events, so does point mutations in Bax. Other mutations that block specific conformational changes in Bax also block the dimerization and/or membrane binding. Our study therefore suggests that Bax interaction in cytosol, binding to membrane and conformational changes are coupled reactions that eventually lead to permeabilization of the mitochondria outer membrane, thereby the potential targets for therapeutic interference. (The work was supported by the NIH grant GM062964 and the OCAST grant HR 10-121 to J.L.)