Cryo-EM structures of the membrane repair protein dysferlin

Hsiang-Ling Huang, Giovanna Grandinetti, Sarah M. Heissler () and Krishna Chinthalapudi ()
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Hsiang-Ling Huang: The Ohio State University College of Medicine
Giovanna Grandinetti: The Ohio State University College of Medicine
Sarah M. Heissler: The Ohio State University College of Medicine
Krishna Chinthalapudi: The Ohio State University College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53773-6

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