Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex
Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex
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DOI：
10.1074/jbc.c700061200
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发表时间：
2007-06-08
影响因子：
4.8
通讯作者：
Campbell, Kevin P.
中科院分区：
文献类型：
--
作者：
Beedle, Aaron M.;Nienaber, Patricia M.;Campbell, Kevin P.
fukutin-related protein（FKRP）的突变引起轻度和更严重形式的肌营养不良症。FKRP患者细胞外蛋白肌营养不良蛋白聚糖的糖基化降低，并且FKRP本身显示出与糖基转移酶的序列相似性，表明FKRP参与了肌营养不良蛋白聚糖的加工。然而，FKRP定位是有争议的，没有FKRP复合物是已知的，所以任何FKRP-肌营养不良蛋白聚糖连接仍然难以捉摸。在这里，我们证明了一种新的FKRP在体内定位;在小鼠中，内源性和重组FKRP都存在于肌膜。生化分析显示，小鼠肌肉FKRP和肌营养不良蛋白聚糖共富集和共断裂，表明FKRP与肌营养不良蛋白聚糖共存于天然肌营养不良蛋白-糖蛋白复合物中。此外，在涉及肌营养不良蛋白-糖蛋白复合物的疾病模型中，FKRP沉降随肌营养不良蛋白聚糖发生变化，肌纤维膜FKRP免疫荧光反映了肌营养不良小鼠中肌营养不良蛋白聚糖的变化，表明FKRP定位可能由肌营养不良蛋白聚糖介导。这些数据提供了肌肉中FKRP复合物的第一个证据，并表明FKRP可能影响肌膜肌营养不良蛋白-糖蛋白复合物内肌营养不良蛋白聚糖的糖基化状态。
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.