Agouti-signaling protein

The agouti-signaling protein (ASIP) is an endogenous antagonist of melanocortin receptors (MCRs) and plays a crucial role in the regulation of pigmentation. ASIP acts normally as a competitive antagonist of melanocortin peptides at MC1R to block cAMP synthesis, leading to the downregulation of eumelanogenesis and the upregulation of pheomelanogenesis. Beyond competitive antagonism, in vitro assays show that this protein can act as an inverse agonist to decrease basal receptor activity in the absence of melanocortin peptides. ASIP also has a role in regulating the lipid metabolism in adipocytes in humans, bovines, and chickens. The ASIP gene encodes a protein with a putative signal peptide sequence and a cysteine-rich C-terminal domain that is sufficient for potent antagonist function. The Arg-Phe-Phe triplet in the C-terminal domains is essential for binding and antagonist function at melanocortin receptors. The N-terminal domain of ASIP acts as a ligand for an accessory receptor, Attractin.