The different ligand-binding modes of relaxin family peptide receptors RXFP1 and RXFP2

Scott, Daniel J., Rosengren, K. Johan and Bathgate, Ross A. D. (2012) The different ligand-binding modes of relaxin family peptide receptors RXFP1 and RXFP2. Molecular Endocrinology, 26 11: 1896-1906. doi:10.1210/me.2012-1188


Author Scott, Daniel J.
Rosengren, K. Johan
Bathgate, Ross A. D.
Title The different ligand-binding modes of relaxin family peptide receptors RXFP1 and RXFP2
Journal name Molecular Endocrinology   Check publisher's open access policy
ISSN 0888-8809
1944-9917
Publication date 2012-11
Sub-type Article (original research)
DOI 10.1210/me.2012-1188
Open Access Status
Volume 26
Issue 11
Start page 1896
End page 1906
Total pages 11
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Collection year 2013
Language eng
Abstract Relaxin and insulin-like peptide 3 (INSL3) are peptide hormones with a number of important physiological roles in reproduction, regulation of extracellular matrix turnover, and cardiovascular function. Relaxin and INSL3 mediate their actions through the closely related G-protein coupled receptors, relaxin family peptide receptors 1 and 2 (RXFP1 and RXFP2), respectively. These receptors have large extracellular domains (ECD) that contain high-affinity ligand-binding sites within their 10 leucine-rich repeat (LRR)-containing modules. Although relaxin can bind and activate both RXFP1 and RXFP2, INSL3 can only bind and activate RXFP2. To investigate whether this difference is related to the nature of the high-affinity ECD binding site or to differences in secondary binding sites involving the receptor transmembrane (TM) domain, we created a suite of constructs with RXFP1/2 chimeric ECD attached to single TM helices. We show that by changing as little as one LRR, representing four amino acid substitutions, we were able to engineer a high-affinity INSL3-binding site into the ECD of RXFP1. Molecular modeling of the INSL3-RXFP2 interaction based on extensive experimental data highlights the differences in the binding mechanisms of relaxin and INSL3 to the ECD of their cognate receptors. Interestingly, when the engineered RXFP1/2 ECD were introduced into full-length RXFP1 constructs, INSL3 exhibited only low affinity and efficacy on these receptors. These results highlight critical differences both in the ECD binding and in the coordination of the ECD-binding site with the TM domain, and provide new mechanistic insights into the binding and activation events of RXFP1 and RXFP2 by their native hormone ligands.
Keyword Relaxin
Insulin-like peptide 3
INSL3
Reproduction
Extracellular matrix turnover
RXFP1
RXFP2
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print: 12 September 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Biomedical Sciences Publications
 
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Created: Mon, 24 Sep 2012, 16:01:52 EST by Bacsweet Kaur on behalf of School of Biomedical Sciences