美国加州大学Z. Hong Zhou团队近期取得重要工作进展。他们通过研究天然DGC结构揭示了肌营养不良致病突变机制。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，杜氏肌营养不良症（DMD）是一种严重的X连锁隐性疾病，其特征是渐进性肌肉萎缩导致过早死亡。编码肌营养不良蛋白的DMD基因的发现不仅揭示了DMD的病因，还帮助鉴定了肌肉细胞膜上至少10种肌营养不良素相关蛋白的家族，共同形成了肌营养不良因子-糖蛋白复合物（DGC）。DGC将细胞外基质与细胞骨架联系起来，但尽管它很重要，其分子结构仍然难以捉摸。

研究人员确定了兔DGC的天然冷冻电镜结构，并进行了生化分析，以揭示其复杂的分子结构。一个意想不到的由β-、γ-和δ-肌聚糖组成的β-螺旋形成了一个细胞外平台，与α-肌聚糖、β-肌聚糖和α-肌糖聚糖相互作用，使α-肌蛋白聚糖与细胞外基质接触。在膜中，肌跨度将β-肌糖基锚定在β-、β-和δ肌聚糖三聚体上，而在细胞质中，β-肌蛋白的膜旁片段结合肌营养不良蛋白的ZZ结构域。通过这些相互作用，DGC将层粘连蛋白2与细胞内肌动蛋白连接起来。

此外，肌营养不良蛋白的WW结构域及其EF-hand 1结构域与α-肌营养不良蛋白连接蛋白相互作用。将致病突变映射到WW结构域会削弱这种相互作用，这一点在生化检测中WW结构区的缺失中得到了证实。

总之，这一研究结果解释了与多种肌营养不良亚型相关的110多种影响单个氨基酸残基的突变，并为包括蛋白质修复、补偿基因上调以及基因替代在内的持续治疗开发提供了贡献。

附：英文原文

Title: Native DGC structure rationalizes muscular dystrophy-causing mutations

Author: Liu, Shiheng, Su, Tiantian, Xia, Xian, Zhou, Z. Hong

Issue&Volume: 2024-12-11

Abstract: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality1,2. Discovery of the DMD gene encoding dystrophin both revealed the cause of DMD and helped identify a family of at least ten dystrophin-associated proteins at the muscle cell membrane, collectively forming the dystrophin–glycoprotein complex (DGC)3,4,5,6,7,8,9. The DGC links the extracellular matrix to the cytoskeleton, but, despite its importance, its molecular architecture has remained elusive. Here we determined the native cryo-electron microscopy structure of rabbit DGC and conducted biochemical analyses to reveal its intricate molecular configuration. An unexpected β-helix comprising β-, γ- and δ-sarcoglycan forms an extracellular platform that interacts with α-dystroglycan, β-dystroglycan and α-sarcoglycan, allowing α-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, while in the cytoplasm, β-dystroglycan’s juxtamembrane fragment binds dystrophin’s ZZ domain. Through these interactions, the DGC links laminin 2 to intracellular actin. Additionally, dystrophin’s WW domain, along with its EF-hand 1 domain, interacts with α-dystrobrevin. A disease-causing mutation mapping to the WW domain weakens this interaction, as confirmed by deletion of the WW domain in biochemical assays. Our findings rationalize more than 110 mutations affecting single residues associated with various muscular dystrophy subtypes and contribute to ongoing therapeutic developments, including protein restoration, upregulation of compensatory genes and gene replacement.

DOI: 10.1038/s41586-024-08324-w

Source: https://www.nature.com/articles/s41586-024-08324-w