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The A-chain of the human relaxin family peptides has distinct roles in the binding and activation of the different relaxin family peptide receptors
University of Kalmar, School of Pure and Applied Natural Sciences.
University of Kalmar, School of Pure and Applied Natural Sciences.ORCID iD: 0000-0003-0113-6535
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2008 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 25, p. 17287-17297Article in journal (Refereed) Published
Abstract [en]

The relaxin peptides are a family of hormones that share a structural fold characterized by two chains, A and B, that are cross-braced by three disulfide bonds. Relaxins signal through two different classes of G-protein-coupled receptors (GPCRs), leucine-rich repeat-containing GPCRs LGR7 and LGR8 together with GPCR135 and GPCR142, now referred to as the relaxin family peptide (RXFP) receptors 1-4, respectively. Although key binding residues have been identified in the B-chain of the relaxin peptides, the role of the A-chain in their activity is currently unknown. A recent study showed that INSL3 can be truncated at the N terminus of its A-chain by up to 9 residues without affecting the binding affinity to its receptor RXFP2 while becoming a high affinity antagonist. This suggests that the N terminus of the INSL3 A-chain contains residues essential for RXFP2 activation. In this study, we have synthesized A-chain truncated human relaxin-2 and -3 (H2 and H3) relaxin peptides, characterized their structure by both CD and NMR spectroscopy, and tested their binding and cAMP activities on RXFP1, RXFP2, and RXFP3. In stark contrast to INSL3, A-chain-truncated H2 relaxin peptides lost RXFP1 and RXFP2 binding affinity and concurrently cAMP-stimulatory activity. H3 relaxin A-chain-truncated peptides displayed similar properties on RXFP1, highlighting a similar binding mechanism for H2 and H3 relaxin. In contrast, A-chain-truncated H3 relaxin peptides showed identical activity on RXFP3, highlighting that the B-chain is the sole determinant of the H3 relaxin-RXFP3 interaction. Our results provide new insights into the action of relaxins and demonstrate that the role of the A-chain for relaxin activity is both peptide- and receptor-dependent. 

Place, publisher, year, edition, pages
2008. Vol. 283, no 25, p. 17287-17297
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-1812DOI: 10.1074/jbc.M801911200OAI: oai:DiVA.org:lnu-1812DiVA, id: diva2:308860
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Structure and function of relaxins
Open this publication in new window or tab >>Structure and function of relaxins
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The relaxin/insulin superfamily is a group of peptide hormones that consists of ten members in human, namely relaxins 1-3, insulin-like peptides (INSL) 3-6, insulin and insulin-like growth factors (IGF) I-II. These peptides have various functions in the body, such as regulating growth, blood glucose levels,  collagen metabolism, germ cell maturation and appetite. Misregulation of these mechanisms is associated with disease and accordingly they are of interest as potential pharmaceutical targets. Structurally the hormones are characterised by two peptide chains, A and B, which are held together by one intra A-chain and two inter chain disulfide bonds. Four different G-protein coupled receptors (GPCR) called relaxin family peptide receptor (RXFP) 1-4 have been found to respond to stimuli by different relaxin peptides. RXFP3 and RXFP4 are classic peptide ligand GPCRs, whereas RXFP1 and RXFP2 are characterised by a large extracellular leucine rich-repeat domain. Relaxin-3, which is the relaxin family ancestor, is the only relaxin peptide known to be able to bind and activate both subtypes of GPCRs, namely RXFP1, RXFP3 and RXFP4.

The aim of this thesis was to analyse the structure-function relationship of the relaxin ligands and receptors, and to use this information to develop selective ligands for the relaxin receptors, which can be used as drug leads or pharmacological tools for investigating the physiological roles of the RXFPs.

The 3D structures of native INSL5 and relaxin-2 were determined by solution NMR spectroscopy. The peptides showed an insulin/relaxin-like overall fold. A relaxin chimera peptide, consisting of the A-chain from INSL5 and the B-chain from relaxin-3, R3/I5, which has been shown to be selective for RXFP3 and RXFP4 over RXFP1, was also subjected to NMR studies. The R3/I5 peptide maintained an insulin/relaxin-like overall fold, and the relaxin-3 B-chain adopted a conformation identical to that in native relaxin-3, confirming that the activity of R3/I5 can be directly related to its primary sequence. Furthermore, a truncation study was undertaken to ascertain the importance of the termini for structure and function. By using the knowledge generated from the structure-function relationship, a single-chain high affinity RXFP3 selective antagonist was developed.

In conclusion, this thesis has contributed to broaden the knowledge of the structure-function relationship of the relaxin ligands and the development of a selective RXFP3 antagonist, which is currently a drug lead for treatment of neurological disorders including stress and obesity.

Place, publisher, year, edition, pages
Växjö, Kalmar: Linneaus University Press, 2011
Series
Linnaeus University Dissertations ; 31/2011
Keywords
relaxin, insulin-like peptide, peptide hormone, peptide synthesis and NMR
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-9793 (URN)978-91-86491-55-0 (ISBN)
Public defence
2011-01-28, N2007, Smålandsgatan 26B, Kalmar, 09:30 (English)
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Available from: 2010-12-21 Created: 2010-12-21 Last updated: 2017-04-18Bibliographically approved

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Rosengren, JohanHaugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.

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