Identification of Two New Cholesterol Interaction Sites on the A2A Adenosine Receptor

Eric Rouviere, Clément Arnarez, Lewen Yang, Edward Lyman

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

By mole, cholesterol is the most abundant component of animal cell plasma membranes. Many membrane proteins have been shown to be functionally dependent on cholesterol, several of which have also been shown to bind cholesterol at well-defined locations on their membrane-facing surface. In this work, a combination of coarse-grained “Martini” and all-atom simulations are used to identify two, to our knowledge, new cholesterol-binding sites on the A2A adenosine receptor, a G-protein-coupled receptor that is a target for the treatment of Parkinson's disease. One of the sites is also observed to bind cholesterol in several recent, high-resolution crystal structures of the protein, and in the simulations, interacts with cholesterol only when bound to the inverse agonist ZM241385. Cataloguing cholesterol-binding sites is a vital step in the effort to understand cholesterol-dependent function of membrane proteins. Given that cholesterol content in plasma membranes varies with cell type and on administration of widely prescribed pharmaceuticals, such as statins, understanding cholesterol-dependent function is an important step toward exploiting membrane compositional variation for therapeutic purposes.

Original languageEnglish
Pages (from-to)2415-2424
Number of pages10
JournalBiophysical Journal
Volume113
Issue number11
DOIs
Publication statusPublished - 5 Dec 2017

    Fingerprint

Cite this