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Molecular Signatures of Cholesterol Interaction with Serotonin Receptors

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Book cover Biochemical and Biophysical Roles of Cell Surface Molecules

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1112))

Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. CSIR-National Chemical Laboratory, Pune, India

    Madhura Mohole, Xavier Prasanna & Durba Sengupta

  2. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India

    Amitabha Chattopadhyay

  3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

    Madhura Mohole & Durba Sengupta

Authors
  1. Madhura Mohole
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  2. Xavier Prasanna
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  3. Durba Sengupta
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  4. Amitabha Chattopadhyay
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Corresponding authors

Correspondence to Durba Sengupta or Amitabha Chattopadhyay .

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Editors and Affiliations

  1. Centre for Protein Science, Design and Engineering, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Mohali, Punjab, India

    Kausik Chattopadhyay

  2. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    Subhash C. Basu

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Mohole, M., Prasanna, X., Sengupta, D., Chattopadhyay, A. (2018). Molecular Signatures of Cholesterol Interaction with Serotonin Receptors. In: Chattopadhyay, K., Basu, S. (eds) Biochemical and Biophysical Roles of Cell Surface Molecules. Advances in Experimental Medicine and Biology, vol 1112. Springer, Singapore. https://doi.org/10.1007/978-981-13-3065-0_11

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