The Influence of Lipid Tail Composition on Bid-Mediated Bax Pore Formation

Abstract

Physical membrane properties are known to influence the function of proteins interacting with lipid bilayers. In the particular case of mitochondrial outer membrane permeabilization by the protein Bax, it is thought that modifications of membrane properties due to, for example, cholesterol overload or lipid oxidation, might have a crucial influence on the process in cells. But what are the physical reasons behind this influence? In this paper, we examine the role of lipid tail composition in mediating the Bax pore formation process when activated by cleaved Bid. We use different fluorescence methods and a reconstituted system to assess this role on different steps in the process. In complement, we use x-ray scattering and molecular dynamics simulations to evaluate the change in membrane thickness and order with change in lipid tail composition. We show that there is an ideal membrane thickness for Bax pore formation. We also show that lipid disorder is crucial in order to allow for both Bid and Bax insertion into the membrane and for their activation, and therefore pore formation.