MBE Advance Access originally published online on July 3, 2007
Molecular Biology and Evolution 2007 24(9):2001-2008; doi:10.1093/molbev/msm134
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Research Articles |
High Diversity in Functional Properties of Melanocortin 1 Receptor (MC1R) in Divergent Primate Species Is More Strongly Associated with Phylogeny than Coat Color
* Department of Neuroscience, Division of Pharmacology, Biomedical Center, Uppsala University, Uppsala, Sweden
Department of Biology, Anglia Ruskin University, Cambridge, United Kingdom
Department of Zoology, University of Cambridge, Cambridge, United Kingdom
E-mail: helgis{at}bmc.uu.se.
Accepted for publication June 18, 2007.
We have characterized the biochemical function of the melanocortin 1 receptor (MC1R), a critical regulator of melanin synthesis, from 9 phylogenetically diverse primate species with varying coat colors. There is substantial diversity in melanocyte-stimulating hormone (MSH) binding affinity and basal levels of activity in the cloned MC1Rs. MSH binding was lost independently in lemur and New World monkey lineages, whereas high basal levels of MC1R activity occur in lemurs and some New World monkeys and Old World monkeys. Highest levels of basal activity were found in the MC1R of ruffed lemurs, which have the E94K mutation that leads to constitutive activation in other species. In 3 species (2 lemurs and the howler monkey), we report the novel finding that binding and inhibition of MC1R by agouti signaling protein (ASIP) can occur when MSH binding has been lost, thus enabling continuing regulation of the melanin type via ASIP expression. Together, these findings can explain the previous paradox of a predominantly pheomelanic coat in the red ruffed lemur (Varecia rubra). The presence of a functional, MSH-responsive MC1R in orangutan demonstrates that the mechanism of red hair generation in this ape is different from the prevalent mechanism in European human populations. Overall, we have found unexpected diversity in MC1R function among primates and show that the evolution of the regulatory control of MC1R activity occurs by independent variation of 3 distinct mechanisms: basal MC1R activity, MSH binding and activation, and ASIP binding and inhibition. This diversity of function is broadly associated with primate phylogeny and does not have a simple relation to coat color phenotype within primate clades.
Key Words: melanocortin • MSH • primate • coat color • G protein-coupled receptor • MC1
Naruya Saitou, Associate Editor