Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA.
Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, USA.
Nat Commun. 2024 Nov 7;15(1):9650. doi: 10.1038/s41467-024-53773-6.
Plasma membrane repair in response to damage is essential for cell viability. The ferlin family protein dysferlin plays a key role in Ca-dependent membrane repair in striated muscles. Mutations in dysferlin lead to a spectrum of diseases known as dysferlinopathies. The lack of a structure of dysferlin and other ferlin family members has impeded a mechanistic understanding of membrane repair mechanisms and the development of therapies. Here, we present the cryo-EM structures of the full-length human dysferlin monomer and homodimer at 2.96 Å and 4.65 Å resolution. These structures define the architecture of dysferlin, ferlin family-specific domains, and homodimerization mechanisms essential to function. Furthermore, biophysical and cell biology studies revealed how missense mutations in dysferlin contribute to disease mechanisms. In summary, our study provides a framework for the molecular mechanisms of dysferlin and the broader ferlin family, offering a foundation for the development of therapeutic strategies aimed at treating dysferlinopathies.
细胞质膜修复对于细胞活力至关重要。ferlin 家族蛋白 dysferlin 在横纹肌的 Ca2+依赖性膜修复中发挥关键作用。dysferlin 突变会导致一系列称为 dysferlinopathies 的疾病。由于 dysferlin 和其他 ferlin 家族成员缺乏结构，阻碍了对膜修复机制和治疗方法的机制理解。在这里，我们呈现了全长人 dysferlin 单体和同源二聚体的 cryo-EM 结构，分辨率分别为 2.96 Å 和 4.65 Å。这些结构定义了 dysferlin 的结构、ferlin 家族特有的结构域和同源二聚化机制，这些对功能至关重要。此外，生物物理和细胞生物学研究揭示了 dysferlin 中的错义突变如何导致疾病机制。总之，我们的研究为 dysferlin 和更广泛的 ferlin 家族的分子机制提供了一个框架，为旨在治疗 dysferlinopathies 的治疗策略的发展提供了基础。
