Structure-Function Analysis of Sarcospan

描述（由申请人提供）：广泛的，长期的目标，这 我们的建议是了解一种新的四跨膜蛋白的结构和功能， 称为“SARCOSPAN”Sarcospan是一个不可分割的组成部分， 肌营养不良蛋白-糖蛋白复合物，并在骨骼和心脏中高度表达 肌肉以及许多非肌肉组织（Crosbie等人，1997年; Crosbie et 例如，1998; Crosbie等人，1999年）。肌营养不良蛋白-糖蛋白复合物（DGC）是 一种结构复合体，跨越肌肉质膜并连接肌肉细胞。 细胞外基质与细胞内细胞骨架。这种结构性 连接对于正常的肌肉功能是至关重要的， 许多形式的肌营养不良症是由基因突变引起的， 肌营养不良蛋白-糖蛋白复合物。几种信号分子的结合 与DGC的关系也表明，这种复合物可能在介导 细胞外-细胞内通讯。此外，横向关联 在DGC的膜组分中， 复杂.假设sarcospan促进蛋白质-蛋白质 肌营养不良蛋白-糖蛋白复合物内的相互作用。这些蛋白质 相互作用显然对生物体之间的物理联系很重要， 细胞外基质和细胞内肌动蛋白网络，并用于预防 肌肉萎缩症 人类sarcospan基因的突变尚未在已知的 常染色体隐性肌营养不良的病例（Crosbie等，2000年）。 然而，这些突变搜索只检查了普遍存在的形式， SSPN，其具有广泛的表达模式。初步数据显示， SSPN的一种新的肌肉特异性形式在骨骼和心脏中表达， 肌肉.我们假设肌肉SSPN内的突变可能导致新的形式 肌肉萎缩症鉴定和表征 肌肉sarcospan将推进我们的理解的作用， 肌营养不良蛋白-糖蛋白复合物在正常肌肉和发病机制 肌肉萎缩症

DESCRIPTION (provided by applicant): The broad, long-term objectives of this proposal are to understand the structure and function of a novel tetraspanin called SARCOSPAN. Sarcospan is an integral component of the dystrophin-glycoprotein complex and is highly expressed in skeletal and cardiac muscles, as well as many non-muscle tissues (Crosbie et al., 1997; Crosbie et al., 1998; Crosbie et al., 1999). The dystrophin-glycoprotein complex (DGC) is a structural complex that spans the muscle plasma membrane and links the extracellular matrix with the intracellular cytoskeleton. This structural linkage is critical for normal muscle function as clearly demonstrated by the many forms of muscular dystrophy that result from mutations in the dystrophin-glycoprotein complex. Association of several signaling molecules with the DGC also suggests that this complex may play a role in mediating extracellular-intracellular communications. Furthermore, lateral associations amongst membrane components of the DGC are critical for function of this complex. It is hypothesized that sarcospan facilitates protein-protein interactions within the dystrophin-glycoprotein complex. These protein interactions are clearly important for the physical linkage between the extracellular matrix and the intracellular actin network and for the prevention of muscular dystrophy. Human mutations within the sarcospan gene have not been identified in known cases of autosomal recessive muscular dystrophy (Crosbie et al., 2000). However, these mutation searches have only examined the ubiquitous form of SSPN, which has a broad expression pattern. Preliminary data demonstrates that a novel, muscle-specific form of SSPN is expressed in skeletal and cardiac muscles. We hypothesize that mutations within muscle-SSPN may cause novel forms of muscular dystrophy. Identification and characterization of this muscle-sarcospan will advance our understanding of the role of the dystrophin-glycoprotein complex in normal muscle and in the pathogenesis of muscular dystrophy.