Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin
Web of Science
AuthorBruell, S; Sethi, A; Smith, N; Scott, DJ; Hossain, MA; Wu, Q-P; Guo, Z-Y; Petrie, EJ; Gooley, PR; Bathgate, RAD
Source TitleScientific Reports
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sSethi, Ashish; Scott, Daniel; Hossain, Mohammed; Petrie, Emma; Gooley, Paul; Bathgate, Ross; Bruell, Shoni
AffiliationFlorey Department of Neuroscience and Mental Health
Biochemistry and Molecular Biology
Medical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsBruell, S., Sethi, A., Smith, N., Scott, D. J., Hossain, M. A., Wu, Q. -P., Guo, Z. -Y., Petrie, E. J., Gooley, P. R. & Bathgate, R. A. D. (2017). Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin. SCIENTIFIC REPORTS, 7 (1), https://doi.org/10.1038/s41598-017-03638-4.
Access StatusOpen Access
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.
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