Functional characterization of a C-terminal splice variant of the human melanocortin 1 receptor.

The melanocortin 1 receptor (MC1R) is a major determinant of skin pigmentation and sensitivity to ultraviolet radiation. When stimulated by its natural agonists, it promotes the switch from synthesis of poorly photoprotective and lightly colored pheomelanins to production of photoprotective and darker eumelanins. In addition to an unusually high number of single nucleotide polymorphisms, the MC1R is expressed as 3 protein-coding splice variants.

Human melanocortin 1 receptor-mediated ubiquitination of nonvisual arrestins. Role of Mahogunin Ring Finger 1 E3 ligase.

Signaling from the melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor (GPCR) crucial for melanocyte proliferation and differentiation, is regulated by cytosolic β-arrestins (ARRBs). MC1R signaling is also negatively modulated by the E3-ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1), whose mutation causes hyperpigmentation, congenital heart defects and neurodegeneration in mice. We showed previously that although MC1R interacts stably with human ARRB1 or ARRB2, only ARRB2 mediates receptor desensitization and internalization.

Melanocortin 1 receptor and skin pathophysiology: beyond colour, much more than meets the eye.

The melanocortin 1 receptor (MC1R), a G protein-coupled receptor preferentially expressed in melanocytes, mediates the pigmentary effects of α melanocyte-stimulating hormone (αMSH). MC1R is also expressed in other cutaneous cell types, particularly keratinocytes and dermal fibroblasts, suggesting non-pigmentary actions of the αMSH/MC1R system. Böhm and Stegemann now report a dramatic effect of mouse Mc1r functional status on susceptibility to skin fibrosis and collagen types I and III metabolism, in a study combining the powerful mouse model provided by the natural Mc1r(e/e) knockout and an established model of skin fibrosis.

Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms.

The melanocortin 1 receptor (MC1R) is a G-protein-coupled receptor (GPCR) crucial for the regulation of melanocyte proliferation and differentiation. MC1R activation by melanocortin hormones triggers the cAMP pathway and stimulates the extracellular-signal-regulated protein kinases ERK1 and ERK2 to promote synthesis of photoprotective eumelanin pigments, among other effects. Signaling from most GPCRs is regulated by the β-arrestin (ARRB) family of cytosolic multifunctional adaptor proteins, which mediate signal termination and endocytosis of GPCR-agonist complexes.

Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling from melanocortin receptor by competition with Galphas.

Mahogunin ring finger-1 (MGRN1) is a RING domain-containing ubiquitin ligase mutated in mahoganoid, a mouse mutation causing coat color darkening, congenital heart defects, high embryonic lethality, and spongiform neurodegeneration. The melanocortin hormones regulate pigmentation, cortisol production, food intake, and body weight by signaling through five G protein-coupled receptors positively coupled to the cAMP pathway (MC1R-MC5R). Genetic analysis has shown that mouse Mgrn1 is an accessory protein for melanocortin signaling that may inhibit MC1R and MC4R by unknown mechanisms.

New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins.

Tyrosinases are widely distributed in nature. They are copper-containing oxidases belonging to the type 3 copper protein family, together with catechol oxidases and haemocyanins. Tyrosinases are essential enzymes in melanin biosynthesis and therefore responsible for pigmentation of skin and hair in mammals, where two more enzymes, the tyrosinase-related proteins (Tyrps), participate in the pathway.

A three-dimensional model of mammalian tyrosinase active site accounting for loss of function mutations.

Tyrosinases are the first and rate-limiting enzymes in the synthesis of melanin pigments responsible for colouring hair, skin and eyes. Mutation of tyrosinases often decreases melanin production resulting in albinism, but the effects are not always understood at the molecular level. Homology modelling of mouse tyrosinase based on recently published crystal structures of non-mammalian tyrosinases provides an active site model accounting for loss-of-function mutations.

Molecular basis of the extreme dilution mottled mouse mutation: a combination of coding and noncoding genomic alterations.

Tyrosinase is the rate-limiting enzyme in melanin biosynthesis. It is an N-glycosylated, copper-containing transmembrane protein, whose post-translational processing involves intracytoplasmic movement from the endoplasmic reticulum to the Golgi and, eventually, to the melanosome. The expression of the tyrosinase (Tyr) gene is controlled by several regulatory regions including a locus control region (LCR) located 15 kb upstream from the promoter region.

Synthesis and selective in vitro anti-melanoma effect of enantiomeric alpha-methyl- and alpha-ethyl-4-S-cysteaminylphenol.

Melanogenesis provides a unique target for the development of antitumour agents specific for malignant melanoma. Among the anti-melanoma compounds we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising anti-melanoma effects. To further improve its efficacy as an anti-melanoma agent, we synthesized the R- and S-enantiomers (99% enantiomer excess) of alpha-methyl- 4-S-cysteaminylphenol (alpha-Me-4-S-CAP) and alpha-ethyl- 4-S-cysteaminylphenol (alpha-Et-4-S-CAP) by coupling 4-hydroxythiophenol with the oxazolines obtained from the (R)- and (S)-enantiomers of 2-amino-1-propanol and 2-amino-1-butanol, respectively.

Fungal egg-parasites of plant-parasitic nematodes from Spanish soils.

We have investigated the presence of fungal egg-parasites in Spanish soils with plant endoparasitic nematodes. Nine out of 68 samples (13%) yielded fungal parasites. The most common (seven strains) was Pochonia chlamydosporia var.

Conformation-dependent post-translational glycosylation of tyrosinase. Requirement of a specific interaction involving the CuB metal binding site.

Tyrosinase, the rate-limiting enzyme in mammalian melanogenesis, is a copper-containing transmembrane glycoprotein. Tyrosinase undergoes a complex post-translational processing before reaching the melanosomal membrane. This processing involves N-glycosylation in several sites, including one located in the CuB copper binding site, movement from the endoplasmic reticulum (ER) to the Golgi, copper binding, and sorting to the melanosome.

Identification of active site residues involved in metal cofactor binding and stereospecific substrate recognition in Mammalian tyrosinase. Implications to the catalytic cycle.

Tyrosinase (Tyr) and tyrosinase-related proteins (Tyrps) 1 and 2 are the enzymes responsible for mammalian melanogenesis. They display high similarity but different substrate and reaction specificities. Loss-of-function mutations lead to several forms of albinism or other pigmentation disorders.