The effects of cholesterol upon membrane proteins

A question of some importance is whether cholesterol in biomembranes can affect the function of membrane proteins. Several systems have now been examined and a number of conflicting ideas have been put forward. Let us first consider what is known about intrinsic protein-cholesterol interactions. 

The evidence to support the idea that many, if not all, membrane proteins possess a immobile, long-lived annulus was of two kinds (a) biochemical and (b) spin-label studies. The first was based upon the fact that to maintain full enzyme activity, at least 30 lipid molecules per protein are required. The second was the presence of an immobile ESR signal at high protein to phospholipid content. Tanford has shown however that phospholipid is not essential for full enzymatic activity and that the hydrophobic fluid environment of a detergent is quite sufficient [75]. Furthermore, deuterium magnetic resonance studies on reconstituted ATPase systems have cast 

Other experiments carried out with sarcoplasmic reticulum membranes gave results that do not support the idea that cholesterol is excluded by a lipid annulus. This work showed that as the cholesterol content of the biomembrane was raised, the enzyme activity decreased [77,78]. Spin-labelled cholesterol has also been used to study this problem with the conclusion that cholesterol does contact the surface of the protein, but with a lower probabihty than does the lipid [79]. 

Experiments with other membrane proteins also show effects due to the presence of cholesterol. Bacteriorhodopsin for example shows a reduction in protein mobility and a lateral segregation of the protein when cholesterol is present [80]. Cholesterol has been shown to have an inhibitory effect upon the Na /K -ATPase. It was suggested this is probably associated with the general effect of reducing phospholipid fluidity [81,82]. The incorporation of cholesterol into membranes of rat kidney fibroblasts caused two cell membrane enzymes, adenylate cyclase and Na /K -ATPase to exhibit decreased activity. The decrease in adenylate cyclase activity was directly proportional to the uptake of cholesterol [83]. 

Effects on the Na pump of erythrocytes when the membrane cholesterol is depleted have been demonstrated. influx was reduced [84] whereas other workers have reported increased Na efflux [85] and increased selectivity of the pump for internal Na [86]. We have simultaneously measured Na and transport via the Na -K pump in thymocytes [87,88]. Cholesterol depletion activated pump-mediated Na efflux but inhibited pump-mediated influx, whereas under normal physiological conditions these two fluxes are stoichiometrically linked [88-90]. Furthermore, the mode of functioning of the pump was altered, i.e. Na -Na exchange instead of the normal Na -K exchange occurred. It was suggested that in this case cholesterol depletion may cause molecular rearrangements of the multimeric enzyme protein within the phospholipid bilayer [89]. 

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