Mutations in Mlph, Encoding a Member of the Rab Effector Family, Cause the Melanosome Transport Defects Observed in leaden Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 18; pp. 10238 - 10243
• Main Authors: Matesic, Lydia E., Yip, Richard, Reuss, Andreé E., Swing, Deborah A., O'Sullivan, T. Norene, Fletcher, Colin F., Copeland, Neal G., Jenkins, Nancy A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.08.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Adaptor Proteins, Signal Transducing; Alleles; Amino Acid Sequence; Amino acids; Animals; ash gene; Base Sequence; Biological Sciences; Carrier Proteins - genetics; Chromosome Mapping; Chromosomes, Artificial, Bacterial - genetics; Complementary DNA; Complementation; d gene; DNA; DNA Primers - genetics; Genetic Complementation Test; Genetic mutation; Genetics; granuphilin; ln gene; Melanocytes; melanophilin; Melanosomes; Melanosomes - metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Multigene Family; Mutation; MyoVa receptors; Phenotypes; Pigmentation Disorders - genetics; Pigments; Proteins; rab GTP-Binding Proteins - genetics; rab27 GTP-Binding Proteins; Rab27a protein; rabphilin-3A; Rodents; Sequence Homology, Amino Acid; Slp3-a protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.181336698

The d, ash, and In coat color mutations provide a unique model system for the study of vesicle transport in mammals. All three mutant loci encode genes that are required for the polarized transport of melanosomes, the specialized, pigment-containing organelles of melanocytes, to the neighboring keratinocytes and eventually into coat hairs. Genetic studies suggest that these genes function in the same or overlapping pathways and are supported by biochemical studies showing that d encodes an actin-based melanosome transport motor, MyoVa, whereas ash encodes Rab27a, a protein that localizes to the melanosome and is postulated to serve as the MyoVa receptor. Here we show that In encodes melanophilin (Mlph), a previously undescribed protein with homology to Rab effectors such as granuphilin, Slp3-a, and rabphilin-3A. Like all of these effectors, Mlph possesses two Zn2+-binding CX2CX 13,14CX2Cmotifs and a short aromatic-rich amino acid region that is critical for Rab binding. However, Mlph does not contain the two Ca2+-binding C2domains found in these and other proteins involved in vesicle transport, suggesting that it represents a previously unrecognized class of Rab effectors. Collectively, our data show that Mlph is a critical component of the melanosome transport machinery and suggest that Mlph might function as part of a transport complex with Rab27a and MyoVa.