Mutations in dopachrome tautomerase (Dct) affect eumelanin/pheomelanin synthesis, but do not affect intracellular trafficking of the mutant protein
| Autor: | Kazumasa Wakamatsu, Francisco Solano, M. Lynn Lamoreux, Shosuke Ito, Gertrude-E. Costin, Adina L. Milac, Yuji Yamaguchi, Vincent J. Hearing, Andrei J. Petrescu, Francois Rouzaud, Wilfred D. Vieira, Julio C. Valencia |
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| Rok vydání: | 2005 |
| Předmět: |
Protein Conformation
Molecular Sequence Data Biology Melanocyte Biochemistry Gene Expression Regulation Enzymologic Melanin Mice Mutant protein medicine Animals Amino Acid Sequence Molecular Biology Cells Cultured Melanins chemistry.chemical_classification Binding Sites Sequence Homology Amino Acid Cell Biology Transmembrane protein Intramolecular Oxidoreductases body regions Protein Transport Transmembrane domain Enzyme medicine.anatomical_structure Membrane protein chemistry Melanocytes Dopachrome tautomerase Research Article |
| Zdroj: | Biochemical Journal. 391:249-259 |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | Dopachrome tautomerase (Dct) is a type I membrane protein and an important regulatory enzyme that plays a pivotal role in the biosynthesis of melanin and in the rapid metabolism of its toxic intermediates. Dct-mutant melanocytes carrying the slaty or slaty light mutations were derived from the skin of newborn congenic C57BL/6J non-agouti black mice and were used to study the effect(s) of these mutations on the intracellular trafficking of Dct and on the pigmentation of the cells. Dct activity is 3-fold lower in slaty cells compared with non-agouti black melanocytes, whereas slaty light melanocytes have a surprisingly 28-fold lower Dct activity. Homology modelling of the active site of Dct suggests that the slaty mutation [R194Q (Arg194→Gln)] is located in the active site and may alter the ability of the enzyme to transform the substrate. Transmembrane prediction methods indicate that the slaty light mutation [G486R (Gly486→Arg)] may result in the sliding of the transmembrane domain towards the N-terminus, thus interfering with Dct function. Chemical analysis showed that both Dct mutations increase pheomelanin and reduce eumelanin produced by melanocytes in culture. Thus the enzymatic activity of Dct may play a role in determining whether the eumelanin or pheomelanin pathway is preferred for pigment biosynthesis. |
| Databáze: | OpenAIRE |
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