Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin

Abstract Relaxin family peptide receptor 2 (RXFP2) is a GPCR known for its role in reproductive function. It is structurally related to the human relaxin receptor RXFP1 and can be activated by human gene-2 (H2) relaxin as well as its cognate ligand insulin-like peptide 3 (INSL3). Both receptors poss...

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Autores principales:	Shoni Bruell, Ashish Sethi, Nicholas Smith, Daniel J. Scott, Mohammed Akhter Hossain, Qing-Ping Wu, Zhan-Yun Guo, Emma J. Petrie, Paul R. Gooley, Ross A. D. Bathgate
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8eaad5d63dd34da1a869adfafa703bc1
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spelling	oai:doaj.org-article:8eaad5d63dd34da1a869adfafa703bc12021-12-02T11:52:58ZDistinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin10.1038/s41598-017-03638-42045-2322https://doaj.org/article/8eaad5d63dd34da1a869adfafa703bc12017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03638-4https://doaj.org/toc/2045-2322Abstract Relaxin family peptide receptor 2 (RXFP2) is a GPCR known for its role in reproductive function. It is structurally related to the human relaxin receptor RXFP1 and can be activated by human gene-2 (H2) relaxin as well as its cognate ligand insulin-like peptide 3 (INSL3). Both receptors possess an N-terminal low-density lipoprotein type a (LDLa) module that is necessary for activation and is joined to a leucine-rich repeat domain by a linker. This linker has been shown to be important for H2 relaxin binding and activation of RXFP1 and herein we investigate the role of the equivalent region of RXFP2. We demonstrate that the linker’s highly-conserved N-terminal region is essential for activation of RXFP2 in response to both ligands. In contrast, the linker is necessary for H2 relaxin, but not INSL3, binding. Our results highlight the distinct mechanism by which INSL3 activates RXFP2 whereby ligand binding mediates reorientation of the LDLa module by the linker region to activate the RXFP2 transmembrane domains in conjunction with the INSL3 A-chain. In contrast, relaxin activation of RXFP2 involves a more RXFP1-like mechanism involving binding to the LDLa-linker, reorientation of the LDLa module and activation of the transmembrane domains by the LDLa alone.Shoni BruellAshish SethiNicholas SmithDaniel J. ScottMohammed Akhter HossainQing-Ping WuZhan-Yun GuoEmma J. PetriePaul R. GooleyRoss A. D. BathgateNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shoni Bruell Ashish Sethi Nicholas Smith Daniel J. Scott Mohammed Akhter Hossain Qing-Ping Wu Zhan-Yun Guo Emma J. Petrie Paul R. Gooley Ross A. D. Bathgate Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
description	Abstract Relaxin family peptide receptor 2 (RXFP2) is a GPCR known for its role in reproductive function. It is structurally related to the human relaxin receptor RXFP1 and can be activated by human gene-2 (H2) relaxin as well as its cognate ligand insulin-like peptide 3 (INSL3). Both receptors possess an N-terminal low-density lipoprotein type a (LDLa) module that is necessary for activation and is joined to a leucine-rich repeat domain by a linker. This linker has been shown to be important for H2 relaxin binding and activation of RXFP1 and herein we investigate the role of the equivalent region of RXFP2. We demonstrate that the linker’s highly-conserved N-terminal region is essential for activation of RXFP2 in response to both ligands. In contrast, the linker is necessary for H2 relaxin, but not INSL3, binding. Our results highlight the distinct mechanism by which INSL3 activates RXFP2 whereby ligand binding mediates reorientation of the LDLa module by the linker region to activate the RXFP2 transmembrane domains in conjunction with the INSL3 A-chain. In contrast, relaxin activation of RXFP2 involves a more RXFP1-like mechanism involving binding to the LDLa-linker, reorientation of the LDLa module and activation of the transmembrane domains by the LDLa alone.
format	article
author	Shoni Bruell Ashish Sethi Nicholas Smith Daniel J. Scott Mohammed Akhter Hossain Qing-Ping Wu Zhan-Yun Guo Emma J. Petrie Paul R. Gooley Ross A. D. Bathgate
author_facet	Shoni Bruell Ashish Sethi Nicholas Smith Daniel J. Scott Mohammed Akhter Hossain Qing-Ping Wu Zhan-Yun Guo Emma J. Petrie Paul R. Gooley Ross A. D. Bathgate
author_sort	Shoni Bruell
title	Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
title_short	Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
title_full	Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
title_fullStr	Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
title_full_unstemmed	Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
title_sort	distinct activation modes of the relaxin family peptide receptor 2 in response to insulin-like peptide 3 and relaxin
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8eaad5d63dd34da1a869adfafa703bc1
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Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin

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