Cryo-EM structures of the membrane repair protein dysferlin
Hsiang-Ling Huang, Giovanna Grandinetti, Sarah M. Heissler, Krishna Chinthalapudi
Abstract
Plasma membrane repair in response to damage is essential for cell viability. The ferlin family protein dysferlin plays a key role in Ca2+-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. Dysferlin is essential for plasma membrane repair, and mutations in this protein cause various muscle diseases. Here the authors report the structure of dysferlin, offering insights into its molecular mechanisms and how mutations impair its function.