Molecular determinants of cholesterol binding to soluble and transmembrane protein domains

Cholesterol-protein interactions play a critical role in lipid metabolism and maintenance of cell integrity. To elucidate the molecular mechanisms underlying these interactions, a growing number of studies have focused on determining the crystal structures of a variety of proteins complexed with cholesterol. These include structures in which cholesterol binds to transmembrane domains, and structures in which cholesterol interacts with soluble ones. However, it remains unknown whether there are differences in the prerequisites for cholesterol binding to these two types of domains. Thus, to define the molecular determinants that characterize the binding of cholesterol to these two distinct protein domains, we employed the database of crystal structures of proteins complexed with cholesterol. Our analysis suggests that cholesterol may bind more strongly to soluble domains than to transmembrane domains. The interactions between cholesterol and the protein in both cases critically depends on hydrophobic and aromatic residues. In addition, cholesterol binding sites in both types of domains involve polar and/or charged residues. However, the percentage of appearance of the different types of polar/charged residues in cholesterol binding sites differs between soluble and transmembrane domains. No differences were observed in the conformational characteristics of the cholesterol molecules bound to soluble versus transmembrane protein domains suggesting that cholesterol is insensitive to the environment provided by the different protein domains.