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MBC in Press, published online ahead of print August 16, 2006
Mol. Biol. Cell 10.1091/mbc.E06-05-0457

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Submitted on May 25, 2006
Accepted on August 9, 2006

A Coiled-Coil Domain of Melanophilin Is Essential for Myosin Va Recruitment and Melanosome Transport in Melanocytes

Alistair N. Hume,* Abul K. Tarafder,* José S. Ramalho,{dagger} Elena V. Sviderskaya,{ddagger} and Miguel C. Seabra*

*Molecular and Cellular Medicine, Division of Biomedical Sciences, Imperial College London, London SW7 2AZ, United Kingdom; {dagger}Centre of Ophthalmology, Biomedical Institute for Research in Light and Image, University of Coimbra, 3000 Coimbra, Portugal; {ddagger}Department of Basic Medical Sciences, St. George’s, University of London, London SW17 0RE, United Kingdom

Monitoring Editor: Jennifer Lippincott-Schwartz

Melanophilin (Mlph) regulates retention of melanosomes at the peripheral actin cytoskeleton of melanocytes, a process essential for normal mammalian pigmentation. Mlph is proposed to be a modular protein the binding melanosome-associated protein Rab27a, Myosin Va (MyoVa), actin and microtubule end-binding protein (EB1), via distinct N-terminal Rab27a binding domain (R27BD), medial MyoVa binding domain (MBD) and C-terminal actin binding domain (ABD), respectively. We developed a novel melanosome transport assay using a Mlph-null cell line to study formation of the active Rab27a:Mlph:MyoVa complex. Recruitment of MyoVa to melanosomes correlated with rescue of melanosome transport and required intact R27BD together with MBD exon F binding region (EFBD) and unexpectedly a potential coiled-coil forming sequence within ABD. In vitro binding studies indicate that the coiled-coil region enhances binding of MyoVa by Mlph MBD. Other regions of Mlph reported to interact with MyoVa globular tail, actin or EB1 are not essential for melanosome transport rescue. The strict correlation between melanosomal MyoVa recruitment and rescue of melanosome distribution, suggests that stable interaction with Mlph and MyoVa activation are nondissociable events. Our results highlight the importance of the coiled-coil region together with R27BD and EFBD regions of Mlph in the formation of active melanosomal Rab27a-Mlph-MyoVa complex.

Address correspondence to: Miguel C. Seabra (m.seabra{at}imperial.ac.uk)




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