Structure of human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework

Haugaard-Jonsson, Linda M., Hossain, Mohammed Akhter, Daly, Norelle L., Craik, David J., Wade, John D. and Rosengren, K. Johan (2009) Structure of human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework. Biochemical Journal, 419 3: 619-627. doi:10.1042/BJ20082353


Author Haugaard-Jonsson, Linda M.
Hossain, Mohammed Akhter
Daly, Norelle L.
Craik, David J.
Wade, John D.
Rosengren, K. Johan
Title Structure of human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework
Journal name Biochemical Journal   Check publisher's open access policy
ISSN 0264-6021
0006-2936
Publication date 2009-05-01
Year available 2009
Sub-type Article (original research)
DOI 10.1042/BJ20082353
Open Access Status Not yet assessed
Volume 419
Issue 3
Start page 619
End page 627
Total pages 9
Place of publication London, U.K.
Publisher Portland Press on behalf of the Biochemical Society
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
060112 Structural Biology (incl. Macromolecular Modelling)
Abstract INSL5 (insulin-like peptide 5) 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 signalling. INSL5 activates the relaxin family peptide receptor 4 with high potency and appears to be the endogenous ligand for this receptor, on the basis of overlapping expression profiles and their apparent co-evolution. In the present study, 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.
Keyword insulin-like peptide 5 (INSL5)
Receptor
NMR
peptide hormone
relaxin
relaxin family peptide receptor (RXFP)
solution-state structure
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 508995
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 03 Sep 2009, 18:10:35 EST by Mr Andrew Martlew on behalf of Institute for Molecular Bioscience