Neurokinin B and serum albumin limit copper binding to mammalian gonadotropin releasing hormone

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

“…The spectrum has a positive signal near 600 nm and a negative signal below 350 nm that correspond to copper d-d transitions and most likely an imidazole → Cu(II) charge transfer transition, respectively [28,31]. Intriguingly, the position of the peaks in the CD spectrum of [Cu II GnRH-II] is identical to that previously obtained from [Cu II GnRH-I] (Figure 1b, dashed line) [32,33]. GnRH-I (pEHWSYGLRPG-NH 2 ) is thought to coordinate Cu(II) via the N-terminal groups, incorporating deprotonated amide nitrogen atoms of the pyroglutamyl ring and His2 and the imidazole nitrogen of His2 with a solvent oxygen contributing to generate a four-coordinate copper site [13].…”

“…These data are consistent with the ESI-MS and CD data. However, the hyperfine splitting at g z for GnRH-II (196.8 × 10 −4 cm −1 ) is larger than that observed for GnRH-I (176.7 × 10 −4 cm −1 ), suggesting that the copper-GnRH-II complex contains more nitrogen donor atoms than the copper-GnRH-I complex [33]. With nitrogen ligands there is often superhyperfine coupling observable at both g z and g x,y that, in many cases, can be used to estimate the number of nitrogen donor atoms [17,35,36].…”

Roles of copper in neurokinin B and gonadotropin-releasing hormone structure and function and the endocrinology of reproduction

“…Spectroscopic evidence suggests that the Cu(II) ion in NKB is in a four-nitrogen environment that includes the histidine imidazole and the amino nitrogen and it is most likely that the Cu(II) ion resides in the ATCUN motif of one of the peptides. The four-nitrogen ATCUN site is predicted to have a higher Cu(II) affinity than the three-nitrogen site seen in GnRH-I and this is observed experimentally because both albumin, which contains a known ATCUN site, and NKB can remove metal from copper-bound GnRH-I (Gul et al, 2018). NKB can form a functional amyloid which allows high concentration packing…”

“…2) (Russino et al, 2013). The affinity of Cu(II) for NKB is higher than that of GnRH, and NKB can strip GnRH of bound metal (Gul et al, 2018). The physiological consequence of this is not clear, but it might suggest that NKB not only shapes GnRH release via its effect on kisspeptin signalling but also fine-tunes or modulates the activity of GnRH by regulating the binding of Cu(II).…”

“…Copper is an essential trace element that is associated with a diversity of protein types, ranging from enzymes to neuropeptides. The metal's role in mammalian reproductive endocrinology was first documented over 80 years ago, but it is only relatively recently that details are emerging of how copper affects the structure and function of neurohormones and neuropeptides involved in reproductive pathways, particularly gonadotropin-releasing hormone (GnRH) (Fevold et al, 1936;Michaluk and Kochman, 2007) and the tachykinin neurokinin B (Russino et al, 2013;Gul et al, 2018). Orthologues and paralogues of mammalian GnRH are present across bilaterian animals and many of these peptides have sequence motifs that are known to coordinate copper, suggesting the metal has a role in their biological functions.…”