The pleomorphic cholesterol sensing motifs of transmembrane proteins

Abstract

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 typesof 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 involverelatively loose contacts between linear amino acid sequences on the membrane-exposed transmembrane domainsof 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 endof this spectrum are more complex cholesterol binding sites that have required the acquisition of complex 3Dnon-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 explorescholesterol-membrane protein interactions using membrane protein paradigms having in common their participationin intercellular communications neurotransmission, hormone signalling, amino acid/neurotransmittertransport- and in cancer.