Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties

Research output: Contribution to journalArticle

Standard

Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties. / Watkins, Harriet A; Chakravarthy, Madhuri; Abhayawardana, Rekhati S; Gingell, Joseph J; Garelja, Michael; Pardamwar, Meenakshi; McElhinney, James M W R; Lathbridge, Alex; Constantine, Arran; Harris, Paul W R; Yuen, Tsz-Ying; Brimble, Margaret A; Barwell, James; Poyner, David R; Woolley, Michael; Conner, Alex C; Pioszak, Augen A; Reynolds, Christopher A; Hay, Debbie L.

In: Journal of Biological Chemistry, 24.03.2016.

Research output: Contribution to journalArticle

Harvard

Watkins, HA, Chakravarthy, M, Abhayawardana, RS, Gingell, JJ, Garelja, M, Pardamwar, M, McElhinney, JMWR, Lathbridge, A, Constantine, A, Harris, PWR, Yuen, T-Y, Brimble, MA, Barwell, J, Poyner, DR, Woolley, M, Conner, AC, Pioszak, AA, Reynolds, CA & Hay, DL 2016, 'Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties', Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M115.688218

APA

Watkins, H. A., Chakravarthy, M., Abhayawardana, R. S., Gingell, J. J., Garelja, M., Pardamwar, M., McElhinney, J. M. W. R., Lathbridge, A., Constantine, A., Harris, P. W. R., Yuen, T-Y., Brimble, M. A., Barwell, J., Poyner, D. R., Woolley, M., Conner, A. C., Pioszak, A. A., Reynolds, C. A., & Hay, D. L. (2016). Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M115.688218

Vancouver

Author

Watkins, Harriet A ; Chakravarthy, Madhuri ; Abhayawardana, Rekhati S ; Gingell, Joseph J ; Garelja, Michael ; Pardamwar, Meenakshi ; McElhinney, James M W R ; Lathbridge, Alex ; Constantine, Arran ; Harris, Paul W R ; Yuen, Tsz-Ying ; Brimble, Margaret A ; Barwell, James ; Poyner, David R ; Woolley, Michael ; Conner, Alex C ; Pioszak, Augen A ; Reynolds, Christopher A ; Hay, Debbie L. / Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties. In: Journal of Biological Chemistry. 2016.

Bibtex

@article{38e1dd969f84464b84b19de96e6728c6,
title = "Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties",
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 (RAMP) 2 and 3, 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 RAMPs 2 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 signalling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modelling 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.",
keywords = "allosteric regulation, cardiovascular disease, conformational change, G protein-coupled receptor (GPCR), molecular modeling, GPCR, RAMP, adrenomedullin, extracellular loops, receptor activity-modifying protein",
author = "Watkins, {Harriet A} and Madhuri Chakravarthy and Abhayawardana, {Rekhati S} and Gingell, {Joseph J} and Michael Garelja and Meenakshi Pardamwar and McElhinney, {James M W R} and Alex Lathbridge and Arran Constantine and Harris, {Paul W R} and Tsz-Ying Yuen and Brimble, {Margaret A} and James Barwell and Poyner, {David R} and Michael Woolley and Conner, {Alex C} and Pioszak, {Augen A} and Reynolds, {Christopher A} and Hay, {Debbie L}",
note = "Copyright {\textcopyright} 2016, The American Society for Biochemistry and Molecular Biology.",
year = "2016",
month = mar
day = "24",
doi = "10.1074/jbc.M115.688218",
language = "English",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology",

}

RIS

TY - JOUR

T1 - Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties

AU - Watkins, Harriet A

AU - Chakravarthy, Madhuri

AU - Abhayawardana, Rekhati S

AU - Gingell, Joseph J

AU - Garelja, Michael

AU - Pardamwar, Meenakshi

AU - McElhinney, James M W R

AU - Lathbridge, Alex

AU - Constantine, Arran

AU - Harris, Paul W R

AU - Yuen, Tsz-Ying

AU - Brimble, Margaret A

AU - Barwell, James

AU - Poyner, David R

AU - Woolley, Michael

AU - Conner, Alex C

AU - Pioszak, Augen A

AU - Reynolds, Christopher A

AU - Hay, Debbie L

N1 - Copyright © 2016, The American Society for Biochemistry and Molecular Biology.

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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 (RAMP) 2 and 3, 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 RAMPs 2 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 signalling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modelling 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.

AB - 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 (RAMP) 2 and 3, 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 RAMPs 2 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 signalling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modelling 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.

KW - allosteric regulation

KW - cardiovascular disease

KW - conformational change

KW - G protein-coupled receptor (GPCR)

KW - molecular modeling

KW - GPCR

KW - RAMP

KW - adrenomedullin

KW - extracellular loops

KW - receptor activity-modifying protein

U2 - 10.1074/jbc.M115.688218

DO - 10.1074/jbc.M115.688218

M3 - Article

C2 - 27013657

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -