The agouti signaling protein (ASIP or the agouti protein) and its neuropeptide homologue the agouti-related protein (AgRP) are paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. ASIP antagonizes the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (MC1R), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). The effect of ASIP on pigment type-switching is responsible for a variety of coat color patterns accross a broad range of mammalian species. AgRP is involved in energy balance and acts normally at the MC3R and MC4R to control body weight regulation and metabolism [, ].Sequence similarity between ASIP and AgRP is confined to their Cys-rich C-terminal domains, which are also responsible for melanocortin receptor binding activity in vitro. Approximately 40 residues in length, there are ten cysteine residues in the C-terminal domain that form a network of five disulfide bonds. The agouti C-terminal domain contains a three-stranded antiparallel beta sheet, where the last two strands form a beta hairpin. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The agouti C-terminal domain adopts the inhibitor cystine knot (ICK) or knottin fold identified in numerous invertebrate toxins [, ].The agouti domain covers the 10 cysteines involved in disulfide bonds.
The agouti signaling protein (ASIP or the agouti protein) and its neuropeptide homologue the agouti-related protein (AgRP) are paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. ASIP antagonizes the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (MC1R), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). The effect of ASIP on pigment type-switching is responsible for a variety of coat color patterns accross a broad range of mammalian species. AgRP is involved in energy balance and acts normally at the MC3R and MC4R to control body weight regulation and metabolism [, ].Sequence similarity between ASIP and AgRP is confined to their Cys-rich C-terminal domains, which are also responsible for melanocortin receptor binding activity in vitro. Approximately 40 residues in length, there are ten cysteine residues in the C-terminal domain that form a network of five disulfide bonds. The agouti C-terminal domain contains a three-stranded antiparallel beta sheet, where the last two strands form a beta hairpin. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The agouti C-terminal domain adopts the inhibitor cystine knot (ICK) or knottin fold identified in numerous invertebrate toxins [, ].This entry represents the agouti domain which covers the 10 cysteines involved in disulfide bonds.
