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

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.