Agouti-Related Protein

AGRP is an endogenous antagonist of melanocortin receptors MC3R and MC4R, and plays a crucial role in the regulation of energy balance. AGRP acts normally as a competitive antagonist of melanocortin peptides at MC3R and MC4R. Beyond competitive antagonism, in vitro assays show that the protein can act as an inverse agonist to decrease basal receptor activity in the absence of melanocortin peptides. AGRP is a single polypeptide protein with a putative signal peptide and a cysteine-rich C-terminal domain which is sufficient for potent antagonist function and possesses very similar protein folds with a usual inhibitor cysteine knot (ICK or knottin) motif stabilized by five disulfide bonds. 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 AGRP acts as a prodomain to be removed by prohormone convertase.