Pigment Type-Switching
Agouti protein is a paracrine signaling molecule produced by specialized cells in the skin that causes melanocytes in the overlying hair follicle to switch from the synthesis of one pigment type, black/brown eumelanin, to an alternative form, red/yellow pheomelanin. Over the past several years, work from our laboratory and others demonstrated that Agouti protein promotes yellow pigment synthesis by binding to and signaling via a G protein–coupled receptor expressed on melanocytes known as the melanocortin 1 receptor (Mc1r).
Besides Agouti and Mc1r, mutations in at least 10 additional genes can interfere with the switching of pigment type. We recently determined that one member of this class encodes Attractin (Atrn), a large single-transmembrane protein that is expressed widely throughout the body but functions in melanocytes as an accessory receptor for Agouti protein. Expression of both Atrn and Mc1r on melanocytes is an absolute requirement for Agouti protein signaling; however, Mc1r lies genetically downstream of Atrn. Furthermore, in the absence of Agouti, mutations of Mc1r but not of Atrn can affect pigmentation. Thus the intracellular effects of Agouti protein signaling are mediated via Mc1r, while cell surface interaction with Atrn permits signaling to take place. Our current effort is directed at understanding the biochemical basis for these observations and is likely to have wider implications for understanding how peptide hormones signal through G protein–coupled receptors.