Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice

Lydia E. Matesic, Richard Yip, Andreé E. Reuss, Deborah A. Swing, T. Norene O'Sullivan, Colin F. Fletcher, Neal G. Copeland, Nancy A. Jenkins

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

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 CX2CX13,14CX2C motifs and a short aromatic-rich amino acid region 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 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.

Original languageEnglish (US)
Pages (from-to)10238-10243
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number18
DOIs
StatePublished - Aug 28 2001

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice'. Together they form a unique fingerprint.

Cite this