KissWiki Basic Biology Structural elements of kisspeptins
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The KiSS-1 gene encodes a large polypeptide consisting of 145 amino acids, known as the pre-peptide to kisspeptins. This pre-peptide contains a 19 amino acid leader sequence that directs the protein into the endoplasmic reticulum (ER) and which gives rise to a secretory precursor protein of 126 amino acids which is proteolytically cleaved and modified to form a C-terminal amide moiety in the Golgi membrane network (Takino et al., 2003).
The kisspeptin-54 (metastin) produced is then cleaved further to equally potent smaller fragments of 14, 13 and 10 amino acids in length. These fragments have subsequently been shown to bind and activate gpr-54 with equal potency (Kotani et al., 2001). Therefore, the final 10 amino acid fragment of the C-terminus has been used to determine the structure of kisspeptins by nuclear magnetic resonance spectroscopy (NMR). Two studies have used NMR to determine the structure; the first used sodium dodecyl sulphate (SDS) micelles NMR method, which represents a negatively charged membrane. In this study kisspeptin-13 was utilised and residues Asn7 to Phe13 were found to form a stable helix structure (Orsini et al., 2007). The second study utilised dodecylphosphocholine (DPC) micelles NMR mechanism which represent a membrane with a neutral charge, similar to the mammalian lipid membrane. Using kisspeptin-10, they showed that Trp3 to Phe10 contained several tight turn structures but no helices. The tight turns contained one β-turn from Tyr3 to Phe6; two miscellaneous type IV β-turns at Asn4 to Gly7 and Gly7 to Phe10; and finally one γ-turn from Ser5 to Gly7 (Lee et al., 2009). This suggests that hydrophobic environments may cause kisspeptins to form a more ordered structure allowing them to bind and activate gpr-54.
The use of NMR to determine the structure of kisspeptin fragments has also shown that hydrogen bonds are important within these peptides, with eight hydrogen bonds being formed within Kisspeptin-13, allowing 16 hydrogen constraints. These are formed between residues Phe9, Leu11, Arg12 and Phe13. These four residues have also been shown to form a pharmacophore which is important for receptor binding. The pharmacophore consists of the phenyl ring of Phe9 with the Phe13 phenyl ring on top. These are then flanked by the positively charged Arg12, which is all in close proximity to the amide moiety. Even though the pharmacophore residues can form hydrogen bonds, it appears that the positive charge is more important for receptor binding (Orsini et al., 2007).
All kisspeptins fragments have also been shown to contain a matrix metalloproteinase (MMP) mediated cleavage site, which is thought to be a mechanism to inactivate the protein. This site is at the C-terminus consisting of Phe-Gly-Leu-Arg, were MMP-2 and MMP-9 can cleave kisspeptin-54 between Gly51 and Leu52. MMPs have also been shown to form a complex with the kisspeptin pre-peptide involving the N-terminal 48 amino acids with Cys53 being critical to this process and the propeptide domain of MMPs (Takino et al., 2003).
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