Mokhonova Ekaterina I, Helzer Daniel, Malik Ravinder, Mamsa Hafsa, Walker Jackson, Maslanka Mark, Fleser Tess S, Afsharinia Mohammad H, Liu Shiheng, Holmberg Johan, Zhou Z Hong, Deeds Eric J, Hansen Kirk C, McNally Elizabeth M, Crosbie Rachelle H
Department of Integrative Biology and Physiology, UCLA, Los Angeles, California, USA.
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Clin Invest. 2025 Jun 19;135(17). doi: 10.1172/JCI187868. eCollection 2025 Sep 2.
The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25 kDa tetraspanin-like protein, anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, supporting the conclusions of biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in δ-sarcoglycanopathies, enabling substitution of δ-sarcoglycan by its homolog, ζ-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that ζ-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protects the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.
肌营养不良蛋白 - 糖蛋白复合体（DGC）由肌细胞膜上的外周膜蛋白和整合膜蛋白组成，这些蛋白将细胞外基质与细胞内细胞骨架连接起来。虽然已知破坏DGC结构完整性的基因突变会导致多种肌肉营养不良症，但该复合体的三维结构一直难以确定。最近两项关于DGC的精妙冷冻电镜结构阐明了其分子结构，并揭示了肌膜联蛋白（SSPN）在该复合体中的独特结构位置。SSPN是一种25 kDa的四跨膜蛋白样蛋白，将β - 肌营养不良聚糖锚定到β -、γ - 和δ - 肌聚糖三聚体上，支持了生化研究得出的结论，即SSPN是DGC组装和稳定的核心元件。在此，我们通过揭示SSPN在δ - 肌聚糖病中提供支架作用，使δ - 肌聚糖能够被其同源物ζ - 肌聚糖替代，从而导致DGC的结构完整性并预防肢带型肌营养不良症R5，推进了这些研究。三维建模显示，ζ - 肌聚糖保留了与肌膜联蛋白、肌聚糖、肌营养不良聚糖和肌营养不良蛋白的蛋白质 - 蛋白质相互作用。该复合体的结构完整性维持了肌纤维与细胞外基质的附着，并保护细胞膜免受收缩诱导的损伤。这些发现表明，肌膜联蛋白通过重塑肌聚糖复合体组成来预防肢带型肌营养不良症R5。
