International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


THE MELANOSOME TRANSPORT DEFECTS OBSERVED IN LEADEN MICE ARE CAUSED BY MUTATIONS IN MLPH, A NOVEL MEMBER OF THE RAB EFFECTOR FAMILY

Lydia Matesic
NCI-Frederick
Mouse Cancer Genetics Program
Bldg 539, Room 234
National Cancer Institute
Frederick 21702, USA

Co-Authors: 1)Wu X, 2)Yip R, 2)Reuss AE, 2)Swing DA, 2)O'Sullivan TN, 3)Fletcher CF, 1)Hammer III JA, 2)Copeland NG, 2)Jenkins NA
Institutions: 1)Laboratory of Cell Biology, National Heart, Lung & Blood Institute, 2) Mouse Cancer Genetics Program, National Cancer Institute, 3)Genomics Institute of the Novartis Research Foundation

The d, ash, and ln coat color mutations provide a unique model system for the study of mammalian vesicular transport. 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 evidence predicts that these genes function in the same or in overlapping pathways and is supported by biochemical studies showing that d encodes an actin-based melanosome transport motor, MyoVa, while ash encodes Rab27a, a protein that localizes to the melanosome and is thought to serve as the MyoVa receptor. Here we demonstrate that ln encodes melanophilin (Mlph), a protein that localizes to the melanosome and has sequence similarity to Rab effectors such as granuphilin, Slp3-a, and rabphilin-3A, all of which are thought to be involved in vesicular trafficking. Like all of these effectors, Mlph possesses two Zn2+-binding motifs and a short region rich in aromatic amino acids that is critical for Rab binding. However, Mlph does not contain the two Ca2+-binding C2 domains found in these and other proteins involved in vesicle transport, suggesting that it is a member of a novel class of Rab effectors. Collectively, our data suggest that Mlph functions as part of a transport complex with Rab27a and with MyoVa.


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