An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

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dc.contributor.author Gingell, Joseph en
dc.contributor.author Simms, J en
dc.contributor.author Barwell, J en
dc.contributor.author Poyner, DR en
dc.contributor.author Watkins, HA en
dc.contributor.author Pioszak, AA en
dc.contributor.author Sexton, PM en
dc.contributor.author Hay, Deborah en
dc.date.accessioned 2016-09-16T06:18:05Z en
dc.date.issued 2016-05-17 en
dc.identifier.citation Cell Discovery, 2016, 2: 16012, pp. 1 - 14 en
dc.identifier.uri http://hdl.handle.net/2292/30390 en
dc.description.abstract G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class. en
dc.description.uri http://www.nature.com/celldisc/ en
dc.publisher Nature Publishing Group en
dc.relation.ispartofseries Cell Discovery en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/2056-5968/ en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri https://creativecommons.org/licenses/by/4.0/ en
dc.title An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology en
dc.type Journal Article en
dc.identifier.doi 10.1038/celldisc.2016.12 en
pubs.begin-page 1 en
pubs.volume 2 en
dc.description.version VoR – Version of Record en
dc.identifier.pmid 27462459 en
pubs.author-url http://www.nature.com/articles/celldisc201612 en
pubs.end-page 14 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype Article en
pubs.elements-id 530433 en
pubs.org-id Science en
pubs.org-id Biological Sciences en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 2056-5968 en
pubs.number 16012 en
pubs.record-created-at-source-date 2016-09-16 en
pubs.dimensions-id 27462459 en


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