Molecular Signatures of Cholesterol Interaction with Serotonin Receptors
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The interaction of G protein-coupled receptors (GPCRs) with cholesterol is a hallmark of their function, organization, and structural dynamics. Several cholesterol interaction sites, such as the cholesterol recognition amino acid consensus (CRAC) and cholesterol consensus motif (CCM), have been mapped from crystallography, bioinformatics, and simulation studies. In this article, we characterize common descriptors for cholesterol interaction sites in the serotonin1A receptor from a series of coarse-grain simulations. We have identified a novel interaction mode for cholesterol in which the cholesterol polar headgroup interacts with aromatic amino acid residues, such as tryptophan and tyrosine. The cholesterol rings interact with both aromatic residues and nonpolar residues, thereby constituting a signature aromatic interaction site. In addition, we report a similar binding mode in the crystal structures of the serotonin2B receptor, suggesting that this binding mode could be a general feature of the serotonin receptor family. Interestingly, this signature aromatic interaction site is present along with one of the CRAC motifs in the serotonin1A receptor. Our results represent an important step toward mapping out the diversity of cholesterol-GPCR interaction sites.
KeywordsGPCR MARTINI coarse-grain simulation Signature aromatic cholesterol interaction site Serotonin receptors Cholesterol interaction site Cholesterol occupancy
This work was supported by the Science and Engineering Research Board (Govt. of India) project (EMR/2016/002294) to A.C. and D.S. A.C. gratefully acknowledges support from J.C. Bose Fellowship (Department of Science and Technology, Govt. of India). M.M. thanks the Department of Biotechnology, Govt. of India, for the award of a Junior Research Fellowship. A.C. is an Adjunct Professor of Tata Institute of Fundamental Research (Mumbai), RMIT University (Melbourne, Australia), Indian Institute of Technology (Kanpur), and Indian Institute of Science Education and Research (Mohali). We acknowledge the CSIR Fourth Paradigm Institute (Bangalore) for computational time. We thank Sreetama Pal for help and members of the Chattopadhyay laboratory for their comments.