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Receptor Activity-modifying Proteins 2 and 3 Generate Adrenomedullin Receptor Subtypes with Distinct Molecular Properties

Watkins, Harriet A and Chakravarthy, Madhuri and Abhayawardana, Rekhati S and Gingell, Joseph J and Garelja, Michael and Pardamwar, Meenakshi and McElhinney, James MWR and Lathbridge, Alex and Constantine, Arran and Harris, Paul WR and Yuen, Tsz-Ying and Brimble, Margaret A and Barwell, James and Poyner, David R and Woolley, Michael J and Conner, Alex C and Pioszak, Augen A and Reynolds, Christopher A and Hay, Debbie L (2016) 'Receptor Activity-modifying Proteins 2 and 3 Generate Adrenomedullin Receptor Subtypes with Distinct Molecular Properties.' Journal of Biological Chemistry, 291 (22). pp. 11657-11675. ISSN 0021-9258

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Abstract

Adrenomedullin (AM) is a peptide hormone with numerous effects in the vascular systems. AM signals through the AM1 and AM2 receptors formed by the obligate heterodimerization of a G protein-coupled receptor, the calcitonin receptor-like receptor (CLR), and receptor activity-modifying proteins 2 and 3 (RAMP2 and RAMP3), respectively. These different CLR-RAMP interactions yield discrete receptor pharmacology and physiological effects. The effective design of therapeutics that target the individual AM receptors is dependent on understanding the molecular details of the effects of RAMPs on CLR. To understand the role of RAMP2 and -3 on the activation and conformation of the CLR subunit of AM receptors, we mutated 68 individual amino acids in the juxtamembrane region of CLR, a key region for activation of AM receptors, and determined the effects on cAMP signaling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modeling of the full-length AM-bound AM1 and AM2 receptors predicted differences in the binding pocket and differences in the electrostatic potential of the two AM receptors. Druggability analysis indicated unique features that could be used to develop selective small molecule ligands for each receptor. The interaction of RAMP2 or RAMP3 with CLR induces conformational variation in the juxtamembrane region, yielding distinct binding pockets, probably via an allosteric mechanism. These subtype-specific differences have implications for the design of therapeutics aimed at specific AM receptors and for understanding the mechanisms by which accessory proteins affect G protein-coupled receptor function.

Item Type: Article
Uncontrolled Keywords: Humans; Crystallography, X-Ray; Sequence Alignment; Amino Acid Sequence; Protein Binding; Models, Molecular; Adrenomedullin; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptors, Adrenomedullin; Calcitonin Receptor-Like Protein
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 23 Jun 2016 16:33
Last Modified: 18 Aug 2022 11:17
URI: http://repository.essex.ac.uk/id/eprint/16995

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