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J. Biol. Chem., Vol. 283, Issue 25, 17287-17297, June 20, 2008

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The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors^*

Mohammed Akhter Hossain, K. Johan Rosengren¹, Linda M. Haugaard-Jönsson, Soude Zhang, Sharon Layfield, Tania Ferraro, Norelle L. Daly^¶, Geoffrey W. Tregear^||, John D. Wade^**, and Ross A. D. Bathgate^||2

From the Howard Florey Institute and ^||Department of Biochemistry and Molecular Biology and the ^**School of Chemistry, University of Melbourne, Victoria 3010, Australia, the School of Pure and Applied Natural Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden, and the ^¶Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

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.

Received for publication, March 10, 2008 , and in revised form, April 22, 2008.

^* This work was supported in part by National Health and Medical Research Council Project Grants 350284 (to J. D. W., G. W. T., and R. A. B.) and 300012 (to R. A. B. and J. D. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by Åke Wiberg's Foundation.

² To whom correspondence should be addressed: Howard Florey Institute, University of Melbourne, Victoria 3010, Australia. Tel.: 61-3-8344-5648; Fax: 61-3-9348-1707; E-mail: bathgate{at}florey.edu.au.

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