西湖大学吴建平等在最新研究中，报道了肌营养不良蛋白糖蛋白复合物的结构和组装。相关研究成果2024年12月11日在线发表于《自然》杂志上。

据介绍，肌营养不良蛋白糖蛋白复合物（DGC）通过将细胞内细胞骨架与周围的细胞外基质连接起来，在维持细胞膜的稳定性和完整性方面发挥着至关重要的作用。肌营养不良素及其相关蛋白的功能障碍会导致肌肉营养不良，这是一种以渐进性肌肉无力和变性为特征的疾病。尽管DGC在生理学和病理学中起着重要作用，但其结构细节在很大程度上仍然未知，阻碍了对其组装和功能的全面理解。

研究人员从小鼠骨骼肌中分离出天然DGC，并获得了其高分辨率结构。这一研究揭示了与之前的DGC组装模型明显不同的结构。具体而言，在细胞外侧，β-、γ-和δ-肌聚糖共折叠形成一种特殊的细胞外塔式结构，该结构通过为α-肌聚糖和肌营养不良蛋白聚糖提供结合位点，在复杂的组装中起着核心作用。

在跨膜区，肌聚糖和肌跨度包围并稳定了单跨膜螺旋的肌聚糖，而不是像以前提出的那样形成亚复合物。在细胞内，肌聚糖和肌营养不良蛋白聚糖通过与肌营养不良蛋白的ZZ结构域的广泛相互作用，与肌营养异不良蛋白-肌营养不良蛋白亚复合物进行组装。

总之，这一研究加深了人们对细胞膜结构联系的理解，并为许多肌肉营养不良相关突变的分子解释提供了基础。

附：英文原文

Title: Structure and assembly of the dystrophin glycoprotein complex

Author: Wan, Li, Ge, Xiaofei, Xu, Qikui, Huang, Gaoxingyu, Yang, Tiandi, Campbell, Kevin P., Yan, Zhen, Wu, Jianping

Issue&Volume: 2024-12-11

Abstract: The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix1,2,3. Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration4,5. Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed6,7,8. On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin–dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.

DOI: 10.1038/s41586-024-08310-2

Source: https://www.nature.com/articles/s41586-024-08310-2