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. 1992 Feb;11(2):527–535. doi: 10.1002/j.1460-2075.1992.tb05083.x

A second tyrosinase-related protein, TRP-2, maps to and is mutated at the mouse slaty locus.

I J Jackson 1, D M Chambers 1, K Tsukamoto 1, N G Copeland 1, D J Gilbert 1, N A Jenkins 1, V Hearing 1
PMCID: PMC556483  PMID: 1537334

Abstract

We have cloned and sequenced mouse cDNAs corresponding to a third member of a family of melanocyte-specific mRNAs, which encode tyrosinase and related proteins. This new member, tyrosinase-related protein-2 (TRP-2), has approximately 40% amino acid identity with the two other proteins in the family and has the same structural features including two copper binding sites, two cysteine-rich regions, a signal peptide and a transmembrane domain. We now show that one of the cysteine-rich regions in this protein family is an 'EGF-like' repeat found in many extracellular and cell surface proteins. The gene encoding TRP-2 maps to mouse chromosome 14, in the region of the coat colour mutation slaty. We show that the TRP-2 of slaty mice has a single amino acid difference from wild-type TRP-2; a substitution of glutamine for arginine in the first copper binding site. TRP-2 is the much sought melanogenic enzyme DOPAchrome tautomerase (DT), which catalyses the conversion of DOPAchrome to 5,6,dihydroxyindole-2-carboxylic acid. Extracts from mice homozygous for the slaty mutation have a 3-fold or more reduction in DT activity, indicating that TRP-2/DT is encoded at the slaty locus, and the missense mutation reduces but does not abolish the enzyme activity.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aroca P., Garcia-Borron J. C., Solano F., Lozano J. A. Regulation of mammalian melanogenesis. I: Partial purification and characterization of a dopachrome converting factor: dopachrome tautomerase. Biochim Biophys Acta. 1990 Sep 14;1035(3):266–275. doi: 10.1016/0304-4165(90)90088-e. [DOI] [PubMed] [Google Scholar]
  2. Bairoch A. PROSITE: a dictionary of sites and patterns in proteins. Nucleic Acids Res. 1991 Apr 25;19 (Suppl):2241–2245. doi: 10.1093/nar/19.suppl.2241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barber J. I., Townsend D., Olds D. P., King R. A. Dopachrome oxidoreductase: a new enzyme in the pigment pathway. J Invest Dermatol. 1984 Aug;83(2):145–149. doi: 10.1111/1523-1747.ep12263381. [DOI] [PubMed] [Google Scholar]
  4. Bennett D. C., Huszar D., Laipis P. J., Jaenisch R., Jackson I. J. Phenotypic rescue of mutant brown melanocytes by a retrovirus carrying a wild-type tyrosinase-related protein gene. Development. 1990 Oct;110(2):471–475. doi: 10.1242/dev.110.2.471. [DOI] [PubMed] [Google Scholar]
  5. Ceci J. D., Kingsley D. M., Silan C. M., Copeland N. G., Jenkins N. A. An interspecific backcross linkage map of the proximal half of mouse chromosome 14. Genomics. 1990 Apr;6(4):673–678. doi: 10.1016/0888-7543(90)90503-m. [DOI] [PubMed] [Google Scholar]
  6. Copeland N. G., Jenkins N. A. Development and applications of a molecular genetic linkage map of the mouse genome. Trends Genet. 1991 Apr;7(4):113–118. doi: 10.1016/0168-9525(91)90455-y. [DOI] [PubMed] [Google Scholar]
  7. Davis C. G. The many faces of epidermal growth factor repeats. New Biol. 1990 May;2(5):410–419. [PubMed] [Google Scholar]
  8. Fleming R. J., Scottgale T. N., Diederich R. J., Artavanis-Tsakonas S. The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster. Genes Dev. 1990 Dec;4(12A):2188–2201. doi: 10.1101/gad.4.12a.2188. [DOI] [PubMed] [Google Scholar]
  9. Giebel L. B., Strunk K. M., King R. A., Hanifin J. M., Spritz R. A. A frequent tyrosinase gene mutation in classic, tyrosinase-negative (type IA) oculocutaneous albinism. Proc Natl Acad Sci U S A. 1990 May;87(9):3255–3258. doi: 10.1073/pnas.87.9.3255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Giebel L. B., Tripathi R. K., Strunk K. M., Hanifin J. M., Jackson C. E., King R. A., Spritz R. A. Tyrosinase gene mutations associated with type IB ("yellow") oculocutaneous albinism. Am J Hum Genet. 1991 Jun;48(6):1159–1167. [PMC free article] [PubMed] [Google Scholar]
  11. Ito S. Reexamination of the structure of eumelanin. Biochim Biophys Acta. 1986 Aug 6;883(1):155–161. doi: 10.1016/0304-4165(86)90146-7. [DOI] [PubMed] [Google Scholar]
  12. Jackson I. J. A cDNA encoding tyrosinase-related protein maps to the brown locus in mouse. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4392–4396. doi: 10.1073/pnas.85.12.4392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jackson I. J., Bennett D. C. Identification of the albino mutation of mouse tyrosinase by analysis of an in vitro revertant. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7010–7014. doi: 10.1073/pnas.87.18.7010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jackson I. J., Chambers D. M., Budd P. S., Johnson R. The tyrosinase-related protein-1 gene has a structure and promoter sequence very different from tyrosinase. Nucleic Acids Res. 1991 Jul 25;19(14):3799–3804. doi: 10.1093/nar/19.14.3799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jackson I. J., Chambers D., Rinchik E. M., Bennett D. C. Characterization of TRP-1 mRNA levels in dominant and recessive mutations at the mouse brown (b) locus. Genetics. 1990 Oct;126(2):451–459. doi: 10.1093/genetics/126.2.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jackson I. J. Mouse coat colour mutations: a molecular genetic resource which spans the centuries. Bioessays. 1991 Sep;13(9):439–446. doi: 10.1002/bies.950130903. [DOI] [PubMed] [Google Scholar]
  17. Jenkins N. A., Copeland N. G., Taylor B. A., Lee B. K. Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus. J Virol. 1982 Jul;43(1):26–36. doi: 10.1128/jvi.43.1.26-36.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kikuchi H., Hara S., Ishiguro S., Tamai M., Watanabe M. Detection of point mutation in the tyrosinase gene of a Japanese albino patient by a direct sequencing of amplified DNA. Hum Genet. 1990 Jun;85(1):123–124. doi: 10.1007/BF00276337. [DOI] [PubMed] [Google Scholar]
  19. Kwon B. S., Haq A. K., Wakulchik M., Kestler D., Barton D. E., Francke U., Lamoreux M. L., Whitney J. B., 3rd, Halaban R. Isolation, chromosomal mapping, and expression of the mouse tyrosinase gene. J Invest Dermatol. 1989 Nov;93(5):589–594. doi: 10.1111/1523-1747.ep12319693. [DOI] [PubMed] [Google Scholar]
  20. Körner A. M., Pawelek J. Dopachrome conversion: a possible control point in melanin biosynthesis. J Invest Dermatol. 1980 Aug;75(2):192–195. doi: 10.1111/1523-1747.ep12522650. [DOI] [PubMed] [Google Scholar]
  21. Körner A., Pawelek J. Mammalian tyrosinase catalyzes three reactions in the biosynthesis of melanin. Science. 1982 Sep 17;217(4565):1163–1165. doi: 10.1126/science.6810464. [DOI] [PubMed] [Google Scholar]
  22. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  23. Mercer J. A., Seperack P. K., Strobel M. C., Copeland N. G., Jenkins N. A. Novel myosin heavy chain encoded by murine dilute coat colour locus. Nature. 1991 Feb 21;349(6311):709–713. doi: 10.1038/349709a0. [DOI] [PubMed] [Google Scholar]
  24. Murray M., Pawelek J. M., Lamoreux M. L. New regulatory factors for melanogenesis: developmental changes in neonatal mice of various genotypes. Dev Biol. 1983 Nov;100(1):120–126. doi: 10.1016/0012-1606(83)90202-6. [DOI] [PubMed] [Google Scholar]
  25. Müller G., Ruppert S., Schmid E., Schütz G. Functional analysis of alternatively spliced tyrosinase gene transcripts. EMBO J. 1988 Sep;7(9):2723–2730. doi: 10.1002/j.1460-2075.1988.tb03126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Oetting W. S., Handoko H. Y., Mentink M. M., Paller A. S., White J. G., King R. A. Molecular analysis of an extended family with type IA (tyrosinase-negative) oculocutaneous albinism. J Invest Dermatol. 1991 Jul;97(1):15–19. doi: 10.1111/1523-1747.ep12477808. [DOI] [PubMed] [Google Scholar]
  27. Oetting W. S., Mentink M. M., Summers C. G., Lewis R. A., White J. G., King R. A. Three different frameshift mutations of the tyrosinase gene in type IA oculocutaneous albinism. Am J Hum Genet. 1991 Jul;49(1):199–206. [PMC free article] [PubMed] [Google Scholar]
  28. Pawelek J. M. Dopachrome conversion factor functions as an isomerase. Biochem Biophys Res Commun. 1990 Feb 14;166(3):1328–1333. doi: 10.1016/0006-291x(90)91011-g. [DOI] [PubMed] [Google Scholar]
  29. Pawelek J. M., Lerner A. B. 5,6-Dihydroxyindole is a melanin precursor showing potent cytotoxicity. Nature. 1978 Dec 7;276(5688):626–628. doi: 10.1038/276627a0. [DOI] [PubMed] [Google Scholar]
  30. Pawelek J., Körner A., Bergstrom A., Bologna J. New regulators of melanin biosynthesis and the autodestruction of melanoma cells. Nature. 1980 Aug 7;286(5773):617–619. doi: 10.1038/286617a0. [DOI] [PubMed] [Google Scholar]
  31. RUSSELL W. L. X-ray-induced mutations in mice. Cold Spring Harb Symp Quant Biol. 1951;16:327–336. doi: 10.1101/sqb.1951.016.01.024. [DOI] [PubMed] [Google Scholar]
  32. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  33. Shibahara S., Okinaga S., Tomita Y., Takeda A., Yamamoto H., Sato M., Takeuchi T. A point mutation in the tyrosinase gene of BALB/c albino mouse causing the cysteine----serine substitution at position 85. Eur J Biochem. 1990 Apr 30;189(2):455–461. doi: 10.1111/j.1432-1033.1990.tb15510.x. [DOI] [PubMed] [Google Scholar]
  34. Shibahara S., Tomita Y., Sakakura T., Nager C., Chaudhuri B., Müller R. Cloning and expression of cDNA encoding mouse tyrosinase. Nucleic Acids Res. 1986 Mar 25;14(6):2413–2427. doi: 10.1093/nar/14.6.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Spritz R. A., Strunk K. M., Giebel L. B., King R. A. Detection of mutations in the tyrosinase gene in a patient with type IA oculocutaneous albinism. N Engl J Med. 1990 Jun 14;322(24):1724–1728. doi: 10.1056/NEJM199006143222407. [DOI] [PubMed] [Google Scholar]
  36. Spritz R. A., Strunk K. M., Hsieh C. L., Sekhon G. S., Francke U. Homozygous tyrosinase gene mutation in an American black with tyrosinase-negative (type IA) oculocutaneous albinism. Am J Hum Genet. 1991 Feb;48(2):318–324. [PMC free article] [PubMed] [Google Scholar]
  37. Takeda A., Tomita Y., Matsunaga J., Tagami H., Shibahara S. Molecular basis of tyrosinase-negative oculocutaneous albinism. A single base mutation in the tyrosinase gene causing arginine to glutamine substitution at position 59. J Biol Chem. 1990 Oct 15;265(29):17792–17797. [PubMed] [Google Scholar]
  38. Takeda A., Tomita Y., Okinaga S., Tagami H., Shibahara S. Functional analysis of the cDNA encoding human tyrosinase precursor. Biochem Biophys Res Commun. 1989 Aug 15;162(3):984–990. doi: 10.1016/0006-291x(89)90770-5. [DOI] [PubMed] [Google Scholar]
  39. Tanaka S., Yamamoto H., Takeuchi S., Takeuchi T. Melanization in albino mice transformed by introducing cloned mouse tyrosinase gene. Development. 1990 Feb;108(2):223–227. doi: 10.1242/dev.108.2.223. [DOI] [PubMed] [Google Scholar]
  40. Thomas U., Speicher S. A., Knust E. The Drosophila gene Serrate encodes an EGF-like transmembrane protein with a complex expression pattern in embryos and wing discs. Development. 1991 Mar;111(3):749–761. doi: 10.1242/dev.111.3.749. [DOI] [PubMed] [Google Scholar]
  41. Tsukamoto K., Jackson I. J., Urabe K., Montague P. M., Hearing V. J. A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase. EMBO J. 1992 Feb;11(2):519–526. doi: 10.1002/j.1460-2075.1992.tb05082.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Winship P. R. An improved method for directly sequencing PCR amplified material using dimethyl sulphoxide. Nucleic Acids Res. 1989 Feb 11;17(3):1266–1266. doi: 10.1093/nar/17.3.1266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yamamoto H., Takeuchi S., Kudo T., Sato C., Takeuchi T. Melanin production in cultured albino melanocytes transfected with mouse tyrosinase cDNA. Jpn J Genet. 1989 Apr;64(2):121–135. doi: 10.1266/jjg.64.121. [DOI] [PubMed] [Google Scholar]
  44. Yokoyama T., Silversides D. W., Waymire K. G., Kwon B. S., Takeuchi T., Overbeek P. A. Conserved cysteine to serine mutation in tyrosinase is responsible for the classical albino mutation in laboratory mice. Nucleic Acids Res. 1990 Dec 25;18(24):7293–7298. doi: 10.1093/nar/18.24.7293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zdarsky E., Favor J., Jackson I. J. The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type. Genetics. 1990 Oct;126(2):443–449. doi: 10.1093/genetics/126.2.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 1986 Jun 11;14(11):4683–4690. doi: 10.1093/nar/14.11.4683. [DOI] [PMC free article] [PubMed] [Google Scholar]

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