Structural insights into the function of relaxins.
The relaxin peptide hormones are members of the insulin superfamily and share a structural fold that is characterized by two peptide chains which are cross-braced by three disulfide bonds. On this framework, various amino acid side chains are presented, allowing specific interactions with different receptors. The relaxin receptors belong to two unrelated classes of G-protein-coupled receptors, but interestingly they are not selective for a single relaxin peptide. Relaxin-3, which is considered to be an extreme example of the relaxin family, can activate receptors from both classes and in fact interacts to some degree with all four receptors identified to date. To deduce how changes in the primary sequence can fine-tune the overall structure and thus the ability to interact with the various receptors, we have studied a range of relaxin-like peptides using solution nuclear magnetic resonance analysis. Three-dimensional structures of relaxin-3, insulin-like peptide 3 (INSL3), and INSL5 were determined and revealed a number of interesting features. All peptides showed a significant amount of line-broadening in certain regions, in particular around the intra-A-chain disulfide bond, suggesting that despite the disulfide bonds the fold is rather dynamic. Although the peptides share a common structural core there are significant differences, particularly around the termini. The structural data in combination with mutational studies provide valuable insights into the structure-activity relationships of relaxins.
Rosengren
K Johan
KJ
School of Pure and Applied Natural Sciences, University of Kalmar, Kalmar, Sweden. johan.rosengren@hik.se
Bathgate
Ross A D
RA
Craik
David J
DJ
Daly
Norelle L
NL
Haugaard-Jönsson
Linda M
LM
Hossain
Mohammed Akhter
MA
Wade
John D
JD
D000595:Amino Acid Sequence; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D036361:Peptide Hormones / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D012065:Relaxin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D036361:Peptide Hormones; C480238:RLN3 protein, human; D043562:Receptors, G-Protein-Coupled; D012065:Relaxin