High diversity in functional properties of melanocortin 1 receptor (MC1R) in divergent primate species is more strongly associated with phylogeny than coat color

• We have characterized the biochemical function of the melanocortin1 receptor (MC1R), a critical regulator of melanin synthesis,from 9 phylogenetically diverse primate species with varyingcoat colors. There is substantial diversity in melanocyte-stimulatinghormone (MSH) binding affinity and basal levels of activityin the cloned MC1Rs. MSH binding was lost independently in lemurand New World monkey lineages, whereas high basal levels ofMC1R activity occur in lemurs and some New World monkeys andOld World monkeys. Highest levels of basal activity were foundin the MC1R of ruffed lemurs, which have the E94K mutation thatleads to constitutive activation in other species. In 3 species(2 lemurs and the howler monkey), we report the novel findingthat binding and inhibition of MC1R by agouti signaling protein(ASIP) can occur when MSH binding has been lost, thus enablingcontinuing regulation of the melanin type via ASIP expression.Together, these findings can explain the previous paradox ofa predominantly pheomelanic coat in the red ruffed lemur (Vareciarubra). The presence of a functional, MSH-responsive MC1R inorangutan demonstrates that the mechanism of red hair generationin this ape is different from the prevalent mechanism in Europeanhuman populations. Overall, we have found unexpected diversityin MC1R function among primates and show that the evolutionof the regulatory control of MC1R activity occurs by independentvariation of 3 distinct mechanisms: basal MC1R activity, MSHbinding and activation, and ASIP binding and inhibition. Thisdiversity of function is broadly associated with primate phylogenyand does not have a simple relation to coat color phenotypewithin primate clades.

Ämnesord

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

Nyckelord

Amino acid sequence

animals

cell line

cercopithecidae/genetics

colobus/genetics

cyclic AMP/metabolism

evolution

molecular

hair color/*genetics

humans

Lemur/genetics

Macaca/genetics

melanocyte-stimulating hormones/metabolism

molecular sequence data

phylogeny

platyrrhini/genetics

Pongo pygmaeus/genetics

primates/classification/*genetics

radioligand assay

receptor

melanocortin

Type 1/*genetics/metabolism

sequence homology

amino acid

MSH

primate

coat color

G protein-coupled receptor

MC1

MEDICINE

MEDICIN

Biology

Biologi

Publikations- och innehållstyp

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art (ämneskategori)