A mirror code for protein-cholesterol interactions in the two leaflets of biological membranes.

EVANS, L.S.; FANTINI, J.; WILLIAMSON, P.T.F.; DI SCALA, C.; BARRANTES, F.J.

Scientific Reports

Nature Publishing Group -Macmillan Publishers Ltd.

Lugar: Londres; Año: 2016 vol. 6 p. 21907 - 21907

Cholesterol controls the activity of a wide range of membrane receptors through specific interactions. Hence, identifying cholesterol recognition motifs is a critical task for understanding signaling receptor function. The membrane-spanning domains of the paradigm neurotransmitter receptor for acetylcholine (AChR) display a series of cholesterol consensus domains (referred to as ?CARC?). Here we use a combination of molecular modeling, lipid monolayer/mutational approaches and NMR spectroscopy to study the binding of cholesterol to a synthetic CARC peptide. The CARC-cholesterol interaction is of high affinity, lipid-specific, concentration-dependent, and sensitive to single-point mutations. The CARC motif is generally located in the outer membrane leaflet and its reverse sequence CRAC in the inner one. Their simultaneous presence within the same transmembrane domain obeys a ?mirror code? controlling protein-cholesterol interactions in the outer and inner membrane leaflets. Deciphering this code enabled us to elaborate guidelines for the detection of cholesterol-binding motifs in any membrane protein.