Structure of human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework
Résumé
Insulin-like peptide 5 (INSL5) is a two-chain peptide hormone related to insulin and relaxin. It was recently discovered through searches of expressed sequence tag databases and although the full biological significance of INSL5 is still being elucidated, high expression in peripheral tissues such as the colon as well as in the brain and hypothalamus, suggests roles in gut contractility and neuroendocrine signaling. INSL5 activates the relaxin family peptide receptor 4 with high potency, and appears to be the endogenous ligand for this receptor, based on overlapping expression profiles and their apparent co-evolution. Here we have used solution state NMR to characterize the three-dimensional structure of synthetic human INSL5. The structure reveals an insulin/relaxin-like fold with three helical segments that are braced by three disulfide bonds and enclose a hydrophobic core. Furthermore, we characterized in detail the hydrogen bond network and electrostatic interactions between charged groups in INSL5 by NMR-monitored temperature and pH titrations and undertook a comprehensive structural comparison with other members of the relaxin family, thus identifying the conserved structural features of the relaxin fold. The B-chain helix, which is the primary receptor-binding site of the relaxins, is longer in INSL5 than in its close relative relaxin-3. As this feature results in a different positioning of the receptor activation domain ArgB23 and TrpB24 it may be an important contributor to the difference in biological activity observed for these two peptides. Overall the structural studies provide mechanistic insights into the receptor selectivity of this important family of hormones.
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