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Abstract
Agouti protein and Agouti-related protein (Agrp) regulate pigmentation and body weight, respectively, by antagonizing melanocortin receptor signaling. A carboxyl-terminal fragment of Agouti protein, Ser73-Cys131, is sufficient for melanocortin receptor antagonism, but Western blot analysis of skin extracts reveals that the electrophoretic mobility of native Agouti protein corresponds to the mature full-length form, His23-Cys131. To investigate the potential role of the amino-terminal residues, we compared the function of full-length and carboxyl-terminal fragments of Agrp and Agouti protein in a sensitive bioassay based on pigment dispersion in Xenopus melanophores. We find that carboxyl-terminal Agouti protein, and all forms of Agrp tested, act solely by competitive antagonism of melanocortin action. However, full-length Agouti protein acts by an additional mechanism that is time- and temperature-dependent, depresses maximal levels of pigment dispersion, and is therefore likely to be mediated by receptor down-regulation. Apparent down-regulation is not observed for a mixture of amino-terminal and carboxyl-terminal fragments. We propose that the phenotypic effects of Agouti in vivo represent a bipartite mechanism: competitive antagonism of agonist binding by the carboxyl-terminal portion of Agouti protein and down-regulation of melanocortin receptor signaling by an unknown mechanism that requires residues in the amino terminus of the Agouti protein.
Highlights
Studies of the mouse coat color Agouti gene have led to the identification of a novel pair of secreted signaling molecules which regulate mammalian pigmentation and body weight
The nonpigmentary effects of ectopic Agouti expression likely reflect the normal function of Agouti-related protein (Agrp),1 a protein expressed in the hypothalamus and adrenal gland that is similar to Agouti protein in size, sequence, and biochemical activity [11, 12]
Using a sensitive bioassay based on ␣-MSH-induced pigment dispersion in Xenopus melanophores, we have previously shown that inhibition of melanocortin signaling by Agouti protein is increased significantly by preincubating melanophores in Agouti protein for several hours prior to the addition of ␣-MSH [25]
Summary
Studies of the mouse coat color Agouti gene have led to the identification of a novel pair of secreted signaling molecules which regulate mammalian pigmentation and body weight. Most evidence suggests Agouti protein and Agrp act as competitive antagonists of melanocortin receptors [17, 22, 23], meaning that their effects are due solely to their ability to inhibit binding of melanocortin receptor agonists such as ␣-MSH. Using a sensitive bioassay based on ␣-MSH-induced pigment dispersion in Xenopus melanophores, we have previously shown that inhibition of melanocortin signaling by Agouti protein is increased significantly by preincubating melanophores in Agouti protein for several hours prior to the addition of ␣-MSH [25] This observation suggested that Agouti protein induces melanocortin receptor down-regulation in addition to its ability to inhibit ␣-MSH binding. If any, post-translational proteolysis of full-length (His23-Cys131) Agouti protein
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