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ABSTRACT Cholesterol is an important molecular component of the plasma membranes of mammalian cells. Its precursor in the sterol biosynthetic pathway, lanosterol, has been argued by Konrad Bloch (Bloch, K. 1965. Science. 150:19-28; 1983. CRC Crit. Rev. Biochem. 14:47-92; 1994. Blonds in Venetian Paintings, the Nine-Banded Armadillo, and Other Essays in Biochemistry. Yale University Press, New Haven, CT.) to also be a precursor in the molecular evolution of cholesterol. We present a comparative study of the effects of cholesterol and lanosterol on molecular conformational order and phase equilibria of lipid-bilayer membranes. By using deuterium NMR spectroscopy on multilamellar lipid-sterol systems in combination with Monte Carlo simulations of microscopic models of lipid-sterol interactions, we demonstrate that the evolution in the molecular chemistry from lanosterol to cholesterol is manifested in the model lipid-sterol membranes by an increase in the ability of the sterols to promote and stabilize a particular membrane phase, the liquid-ordered phase, and to induce collective order in the acyl-chain conformations of lipid molecules. We also discuss the biological relevance of our results, in particular in the context of membrane domains and rafts.
INTRODUCTION
Cholesterol is the sterol molecule universally present in mammalian cells. It is predominantly distributed in the cell plasma membrane, amounting to 30-50 mol % of the total lipid fraction of the membrane. Given the fact that a plasma membrane consists of >200 lipid species and that the lipid composition varies greatly from one cell type to another, the presence of cholesterol certainly appears strikingly singular. At the level of molecular structure, cholesterol, while being amphiphilic, also differs significantly from the other lipid species. Its hydrophobic part consists chemically of a planar steroid ring and a short hydrocarbon tail (Fig. 1 a). Consequently, this part of the molecule is physically rigid and smooth at atomic scale (Fig. 1 b). This molecular characteristic has important implications for the interactions of cholesterol with other lipid species.
A considerable amount of research has been carried out during the last few decades to elucidate the biological functions of cholesterol in cells, to understand the physical basis for the biological functions by investigating the role of cholesterol in modulating physical properties of artificial and biological membranes, and to unravel the relationship between the functions and the...