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J. Biol. Chem., Vol. 282, Issue 23, 16713-16717, June 8, 2007

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Fukutin-related Protein Associates with the Sarcolemmal Dystrophin-Glycoprotein Complex^*

From the Howard Hughes Medical Institute (HHMI) and the Departments of Molecular Physiology and Biophysics, Internal Medicine, and Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

Mutations in fukutin-related protein (FKRP) give rise to mild and more severe forms of muscular dystrophy. FKRP patients have reduced glycosylation of the extracellular protein dystroglycan, and FKRP itself shows sequence similarity to glycosyltransferases, implicating FKRP in the processing of dystroglycan. However, FKRP localization is controversial, and no FKRP complexes are known, so any FKRP-dystroglycan link remains elusive. Here, we demonstrate a novel FKRP localization in vivo; in mouse, both endogenous and recombinant FKRP are present at the sarcolemma. Biochemical analyses revealed that mouse muscle FKRP and dystroglycan co-enrich and co-fractionate, indicating that FKRP coexists with dystroglycan in the native dystrophin-glycoprotein complex. Furthermore, FKRP sedimentation shifts with dystroglycan in disease models involving the dystrophin-glycoprotein complex, and sarcolemmal FKRP immunofluorescence mirrors that of dystroglycan in muscular dystrophy mice, suggesting that FKRP localization may be mediated by dystroglycan. These data offer the first evidence of an FKRP complex in muscle and suggest that FKRP may influence the glycosylation status of dystroglycan from within the sarcolemmal dystrophin-glycoprotein complex.

Received for publication, March 30, 2007 , and in revised form, April 17, 2007.

^* This work was funded in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant, the Muscular Dystrophy Association, and U.S. Department of Defense Grant W81XWH-05-1-0334. 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.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures and three supplemental tables.

¹ Recipient of Alberta Heritage Foundation for Medical Research and Peter A. Getting Postdoctoral Award support.

² An investigator of HHMI. To whom correspondence should be addressed: HHMI, Dept. of Molecular Physiology and Biophysics, University of Iowa, 4283 Carver Biomedical Research Bldg., 285 Newton Rd., Iowa City, IA 52242. Fax: 319-335-6957; E-mail: kevin-campbell{at}uiowa.edu.

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