Challenges and approaches to understand cholesterol-binding impact on membrane protein function: an NMR view

Experimental evidence for a direct role of lipids in determining the structure, dynamics, and function of membrane proteins leads to the term ‘functional lipids’. In particular, the sterol molecule cholesterol modulates the activity of many membrane proteins. The precise nature of cholesterol-binding sites and the consequences of modulation of local membrane micro-viscosity by cholesterol, however, is often unknown. Here, we review the current knowledge of the interaction of cholesterol with transmembrane proteins, with a special focus on structural aspects of the interaction derived from nuclear magnetic resonance approaches. We highlight examples of the importance of cholesterol modulation of membrane protein function, discuss the specificity of cholesterol binding, and review the proposed binding motifs from a molecular perspective. We conclude with a short perspective on what could be future trends in research efforts targeted towards a better understanding of cholesterol/membrane protein interactions.