Agouti family

The agouti-signaling protein (ASIP) and agouti-related protein (AGRP) are endogenous antagonists of melanocortin receptors (MCRs). They play crucial roles in the regulation of pigmentation and energy balance, respectively, and are thought to have arisen from a common ancestral gene early in vertebrate evolution. ASIP acts normally as a competitive antagonist of melanocortin peptides at MC1R, and AGRP at both MC3R and MC4R. Beyond competitive antagonism, in vitro assays show that they act as inverse agonists to decrease basal receptor activity in the absence of melanocortins. In humans, AGRP and ASIP are 132-aa proteins with putative signal peptide sequences and conserved cysteine-rich C-terminal domains that are sufficient for potent antagonist function. The Arg-Phe-Phe triplet in the C-terminal domains is essential for binding and antagonist function at their cognate melanocortin receptors.