The infection of HIV virus may destroy human lymphocytes and thus weakens the immune system. It is important to understand how HIV virus particles recognize their target cells and penetrate into them. Besides the well-known gp120 glycoprotein, the membrane receptor CXCR4 was found to be a co-receptor for HIV infection. Experimental results showed that CXCR4 function requires a certain cholesterol concentration in the membrane. Based on a newly resolved crystal structure of CXCR4 , we predicted a cholesterol-binding site in the groove between transmembrane helices 1 and 7 by docking calculations and by protein sequence analysis. The two residues (lysine and tyrosine) that were proposed as key features for cholesterol-binding motif (known as CRAC motif) are also present in our predicted binding site and these two residues are conserved among various species. The amino group of lysine K67 establishes a hydrogen bond with the hydroxyl group of cholesterol, whereas tyrosine Y302 stacks with cholesterol by its aromatic side chain. We propose that mutations of residues in our predicted cholesterol-binding site will make CXCR4 less sensitive to membrane cholesterol content.

How cholesterol may mediate fusion of HIV to host cell membranes via the CXCR4-coreceptor

246th National Meeting (2013)

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