Membrane Cholesterol Association and Structure of Two Leukotoxin Peptides

Abstract

The study of membrane effects on protein structure and functioning is relevant to understanding many native cell processes as well as the cytotoxic effects of some proteins. The cholesterol recognition/interaction amino acid consensus (CRAC) motif is a primary structure pattern that is common among many proteins which interact with cholesterol, a key membrane component. However, the CRAC pattern alone is not sufficient to determine the cholesterol-binding ability of a protein. Of two regions which fit the CRAC criteria from a leukotoxin LtxA produced by a pathogenic bacterium, only one is responsible for the cholesterol binding of the toxin. Molecular dynamics simulation of peptides corresponding to both regions reveals that, despite the peptides sharing similar structural characteristics in a solution environment, this comparison is lost near a cholesterol-bearing bilayer. Near such a bilayer, the cholesterol-binding sequence shows a significant loss of secondary structure upon association with the membrane. Furthermore, these results were not observed near a pure phospholipid bilayer, indicating that this behavior is specific to cholesterol-containing membranes.