Copper(II) Binding by the Earliest Vertebrate Gonadotropin-Releasing Hormone, the Type II Isoform, Suggests an Ancient Role for the Metal

In vertebrate reproductive biology copper can influence peptide and protein function both in the pituitary and in the gonads. In the pituitary, copper binds to the key reproductive peptides gonadotropin-releasing hormone I (GnRH-I) and neurokinin B, to modify their structure and function, and in the male gonads, copper plays a role in testosterone production, sperm morphology and, thus, fertility. In addition to GnRH-I, most vertebrates express a second isoform, GnRH-II. GnRH-II can promote testosterone release in some species and has other non-reproductive roles. The primary sequence of GnRH-II has remained largely invariant over millennia, and it is considered the ancestral GnRH peptide in vertebrates. In this work, we use a range of spectroscopic techniques to show that, like GnRH-I, GnRH-II can bind copper. Phylogenetic analysis shows that the proposed copper-binding ligands are retained in GnRH-II peptides from all vertebrates, suggesting that copper-binding is an ancient feature of GnRH peptides.