The pleomorphic cholesterol sensing motifs of transmembrane proteins

Millions of years of phylogenetic evolution have shaped the crosstalk between sterols and membrane-embedded proteins. This lengthy process, which began before the appearance of eukaryotic cells, has sculpted the two types of molecules to cover a wide spectrum of structural interconnectedness, ranging from rapid touch-and-go hits of low-affinity between surfaces to stronger lock-and-key type structural contacts. The former usually involve relatively loose contacts between linear amino acid sequences on the membrane-exposed transmembrane domains of the protein, readily accessible to the sterols as they briefly visit clefts between adjacent transmembrane segments while in rapid exchange with the bulk lipid bilayer. This operational mode is probably the most ancestral one, since it was already present in primitive bacteria interacting with hopanoid lipids. At the other end of this spectrum are more complex cholesterol binding sites that have required the acquisition of complex 3D non-sequential segments of the membrane protein to establish stereochemically elaborate 3D designs complementary to the rough and smooth surfaces of the eukaryotic neutral lipid, cholesterol. This short review explores cholesterol-membrane protein interactions using membrane protein paradigms having in common their participation in intercellular communications neurotransmission, hormone signalling, amino acid/neurotransmitter transport- and in cancer.