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J. Biol. Chem., Vol. 281, Issue 30, 21198-21208, July 28, 2006

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The Repeat Domain of the Melanosomal Matrix Protein PMEL17/GP100 Is Required for the Formation of Organellar Fibers^*

Toshihiko Hoashi¹, Jacqueline Muller^¶, Wilfred D. Vieira, Francois Rouzaud, Kanako Kikuchi, Kunihiko Tamaki, and Vincent J. Hearing²

From the Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892-4256, the ^¶Division of Viral Products, Food and Drug Administration, Rockville, Maryland 20852, and the Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan

Over 125 pigmentation-related genes have been identified to date. Of those, PMEL17/GP100 has been widely studied as a melanoma-specific antigen as well as a protein required for the formation of fibrils in melanosomes. PMEL17 is synthesized, glycosylated, processed, and delivered to melanosomes, allowing them to mature from amorphous round vesicles to elongated fibrillar structures. In contrast to other melanosomal proteins such as TYR and TYRP1, the processing and sorting of PMEL17 is highly complex. Monoclonal antibody HMB45 is commonly used for melanoma detection, but has the added advantage that it specifically reacts with sialylated PMEL17 in the fibrillar matrix in melanosomes. In this study, we generated mutant forms of PMEL17 to clarify the subdomain of PMEL17 required for formation of the fibrillar matrix, a process critical to pigmentation. The internal proline/serine/threonine-rich repeat domain (called the RPT domain) of PMEL17 undergoes variable proteolytic cleavage. Deletion of the RPT domain abolished its recognition by HMB45 and its capacity to form fibrils. Truncation of the C-terminal domain did not significantly affect the processing or trafficking of PMEL17, but, in contrast, deletion of the N-terminal domain abrogated both. We conclude that the RPT domain is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles.

Received for publication, February 21, 2006 , and in revised form, April 4, 2006.

^* This work was supported in part by the Intramural Research Program of the NCI Center for Cancer Research, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. Tel.: 81-3-5800-8661; Fax: 81-3-3814-1503; E-mail: thoashi-tky{at}umin.ac.jp. ² To whom correspondence may be addressed: Lab. of Cell Biology, NIH, Bldg. 37, Rm. 2132, Bethesda, MD 20892-4256. Tel.: 301-496-1564; Fax: 301-402-8787; E-mail: hearingv{at}nih.gov.

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