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J. Biol. Chem., Vol. 283, Issue 46, 32099-32109, November 14, 2008

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Regulation of Receptor Signaling by Relaxin A Chain Motifs

DERIVATION OF PAN-SPECIFIC AND LGR7-SPECIFIC HUMAN RELAXIN ANALOGS^*

Jae-Il Park, Jenia Semyonov¹, Wei Yi, Chia Lin Chang, and Sheau Yu Teddy Hsu²

From the Reproductive Biology and Stem Cell Research Program, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317 and the Department of Obstetrics and Gynecology, Chang Gung University School of Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

Relaxin peptides are important hormones for the regulation of reproductive tissue remodeling and the renal cardiovascular system during pregnancy. Recent studies demonstrated that two of the seven human relaxin family peptides, relaxin H2 (RLN2) and INSL3, signal exclusively through leucine-rich repeat-containing G protein-coupled receptors, LGR7 and LGR8. Although it was well characterized that an RXXXRXXI motif at the RLN2 B chain confers receptor activation activity, it is not clear what roles RLN2 A chain plays in receptor interaction. Analyses of relaxin family genes on syntenic regions of model tetrapods showed that the A chain of RLN2 orthologs exhibited a greater sequence divergence as compared with the receptor-binding domain-containing B chain, foreshadowing a potential role in receptor interactions; hence, defining receptor selectivity in this fast evolving peptide hormone. To test our hypothesis that select residues in the human RLN2 A chain play key roles in receptor interaction, we studied mutant peptides with residue substitution(s) in the A chain. Here, we showed that alanine substitution at the A16 and A17 positions enhances LGR8-activation activity of RLN2, whereas mutation at the A22-23 region (RLN2^A22-23) ablates LGR8, but not LGR7, activation activity. In addition, we demonstrated that the functional characteristics of the RLN2^A22-23 mutant are mainly attributed to modifications at the Phe^A23 position. Taken together, our studies indicated that Thr^A16, Lys^A17, and Phe^A23 constitute part of the receptor-binding interface of human RLN2, and that modification of these residues has led to the generation of novel human RLN2 analogs that would allow selective activation of human LGR7, but not LGR8, in vivo.

Received for publication, September 3, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant R21 HD47606 (to S. Y. H.). This work was also supported by a March of Dimes research grant (to S. Y. H.). 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.

¹ Supported by Bioinformatics Core of the SCCPIR Center, Stanford University School of Medicine, National Institutes of Health Grant HD31398.

² To whom correspondence should be addressed: 300 Pasteur Dr., Rm. A344D, Stanford, CA 94305-5317. Tel.: 650-723-7057; Fax: 650-725-7102; E-mail: teddyhsu{at}stanford.edu.

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