Comparative Analysis of Melanins and Melanosomes Produced by Various Coat Color Mutants

Prota, Giuseppe; Lamoreux, M. Lynn; Müller, Jacqueline; Kobayashi, Takashi; Napolitano, Alessandra; Vincensi, M. R.; Sakai, Chie; Hearing, Vincent J.

doi:10.1111/j.1600-0749.1995.tb00657.x

Cited by 74 publications

(69 citation statements)

References 44 publications

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“…Several clues about the important role of Tyrp1 in Tyr function have also been provided by in vivo studies. Tyr catalytic function in the skin of brown mice is only 80% that found in the skin of black mice (36), and melanin content of brown mouse hair is only 30 -35% that found in black mouse hair (19,36).…”

Section: Tyrp1 Stabilization Of Tyrosinasementioning

confidence: 87%

Tyrosinase Stabilization by Tyrp1 (the brown Locus Protein)

Kobayashi¹,

Imokawa²,

Bennett³

et al. 1998

Journal of Biological Chemistry

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199

154

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Mammalian melanogenesis is regulated directly or indirectly by over 85 distinct loci. The Tyr/albino locus, in which mutations cause a lack of pigmentation, encodes tyrosinase (Tyr), the critical and rate-limiting melanogenic enzyme. Other melanogenic enzymes include Tyrp1 (or TRP1) and 3,4-dihydroxyphenylalaninechrome tautomerase (Dct or TRP2) encoded at the Tyrp1/brown and Dct/slaty loci, respectively. Murine Tyrp1 can oxidize 5,6-dihydroxyindole-2-carboxylic acid (DHICA) produced by Dct, but mutations in Tyrp1 also affect the catalytic functions of Tyr. All three enzymes are membrane-bound melanosomal proteins with similar structural features and are thought to interact within and stabilize a melanogenic complex. We have now further investigated the effect of a Tyrp1 b mutation on Tyr stability. Pulse/chase labeling experiments show that Tyr is degraded more quickly in Tyrp1 b mutant melanocytes than in melanocytes wild type at that locus. This reduced stability of Tyr can be partly rescued by infection with the wild type Tyrp1 gene, and this is accompanied by phenotypic rescue of infected melanocytes. In sum, these results suggest that, in addition to its catalytic function in oxidizing DHICA, Tyrp1 may play an important role in stabilizing Tyr, a second potential role in the regulation of melanin formation.Tyrosinase-related protein 1 (Tyrp1, also known as TRP1 and gp75) is encoded by the Tyrp1/brown locus, one of more than 85 genes that directly or indirectly affect coat color in mice (1-4). Tyrp1 is expressed specifically in melanocytes and functions in melanin synthesis within melanosomes, as do the other members of the tyrosinase-related protein (TRP) 1 family, which includes Tyr (also known as tyrosinase), and Dct (also known as DOPAchrome tautomerase and TRP2). Although TRPs have many similar structural features, including a transmembrane region, two metal-binding regions, and a cysteinerich epidermal growth factor motif, each member of the TRP family has a distinct catalytic activity in the biosynthesis of the melanin biopolymer. Tyr, encoded by the Tyr/albino locus, catalyzes the critical and rate-limiting step of tyrosine hydroxylation to 3,4-dihydroxyphenylalanine (DOPA), DOPA oxidation to DOPAquinone, and 5,6-dihydroxyindole (DHI) oxidation to indole-5,6-quinone (5-7). Dct, encoded by the Dct/slaty locus, functions as DOPAchrome tautomerase, producing DHI-2-carboxylic acid (DHICA) from DOPAchrome rather than the spontaneously decarboxylated product DHI (8, 9). Although Tyrp1 was the first member of the TRP family to be cloned (10), its specific function in melanogenesis has been controversial (11-15). Recently we have shown that murine Tyrp1 functions as a DHICA oxidase in the melanogenic pathway (16,17). This catalytic activity of Tyrp1 promotes the oxidation and polymerization of DHICA monomers into melanin, and in fact, melanins in the hair of brown mice are significantly less polymerized than those in black mice (18,19). There are other distinct differences in DHI-and DHICA-derived melanins, ...

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Section: Tyrp1 Stabilization Of Tyrosinasementioning

confidence: 87%

Tyrosinase Stabilization by Tyrp1 (the brown Locus Protein)

Kobayashi¹,

Imokawa²,

Bennett³

et al. 1998

Journal of Biological Chemistry

Self Cite

199

154

View full text Add to dashboard Cite

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“…Previous studies carried out by us and others have shown that binding of the radiolabeled melanocortins NDP-MSH or ACTH to whole cells can be inhibited by recombinant Agouti protein (Lu et al 1994;Blanchard et al 1995;Siegrist et al 1997;Yang et al 1997 Geschwind (1966), Kobayashi et al (1995), Movaghar (1989), and Prota et al (1995), and as modified from Barsh (1996). During the switch from eumelanin to pheomelanin production caused by increased Agouti expression, tyrosinase activity is gradually downregulated.…”

Section: The Mc1r Is An Agouti Receptormentioning

confidence: 96%

Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo

Mm¹,

Ml²,

Bd³

et al. 1998

Genes & Development

214

148

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Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively. These proteins antagonize the effects of ␣-melanocyte-stimulating hormone (␣-MSH) and other melanocortins, and several alternatives have been proposed to explain their biochemical mechanisms of action. We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity. In melanophores, Agouti protein has no effect in the absence of ␣-MSH, but its action cannot be explained solely by inhibition of ␣-MSH binding. In

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“…Current data suggest that Bloc1 is involved in the sorting and budding of Tyr-and Tyrp1-containing vesicles from the trans-Golgi network, while Bloc2 may be involved in targeting or mediating fusion between small vesicles containing Tyr and/or Tyrp1 in the forming melanosome ( Figure 7D) (Wei 2006;Di Pietro et al 2006;Helip-Wooley et al 2007;Setty et al 2007;Huizing et al 2008;Sitaram and Marks 2012). Interestingly, eumelanin production requires Tyr, Tyrp1, and Tyrp2, while pheomelanogenesis requires only Tyr (Prota et al 1995). Although untested, our data are consistent with the hypothesis that, in the snw/hps5 I76N mutant, reduced Bloc2-dependent transport of Tyrp1 inhibits eumelanosome biogenesis ( Figure 7D).…”

Section: Hps5/hps6 Interaction Is Destabilized By I76nmentioning

confidence: 99%

snow white, a Zebrafish Model of Hermansky-Pudlak Syndrome Type 5

et al. 2013

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Hermansky-Pudlak Syndrome (HPS) is a set of genetically heterogeneous diseases caused by mutations in one of nine known HPS genes. HPS patients display oculocutaneous hypopigmentation and bleeding diathesis and, depending on the disease subtype, pulmonary fibrosis, congenital nystagmus, reduced visual acuity, and platelet aggregation deficiency. Mouse models for all known HPS subtypes have contributed greatly to our understanding of the disease, but many of the molecular and cellular mechanisms underlying HPS remain unknown. Here, we characterize ocular defects in the zebrafish (Danio rerio) mutant snow white (snw), which possesses a recessive, missense mutation in hps5 (hps5 I76N ). Melanosome biogenesis is disrupted in snw/hps5 mutants, resulting in hypopigmentation, a significant decrease in the number, size, and maturity of melanosomes, and the presence of ectopic multimelanosome clusters throughout the mutant retina and choroid. snw/hps5 I76N is the first Hps5 mutation identified within the N-terminal WD40 repeat protein-protein binding domain. Through in vitro coexpression assays, we demonstrate that Hps5 I76N retains the ability to bind its protein complex partners, Hps3 and Hps6. Furthermore, while Hps5 and Hps6 stabilize each other's expression, this stabilization is disrupted by Hps5 I76N . The snw/hps5 I76N mutant provides a valuable resource for structure-function analyses of Hps5 and enables further elucidation of the molecular and cellular mechanisms underlying HPS.

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Comparative Analysis of Melanins and Melanosomes Produced by Various Coat Color Mutants

Cited by 74 publications

References 44 publications

Tyrosinase Stabilization by Tyrp1 (the brown Locus Protein)

Tyrosinase Stabilization by Tyrp1 (the brown Locus Protein)

Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo

snow white, a Zebrafish Model of Hermansky-Pudlak Syndrome Type 5

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