Cryo-EM structures of the membrane repair protein dysferlin.

Autor: Huang HL; Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA., Grandinetti G; 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., Heissler SM; Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA. sarah.heissler@osumc.edu., Chinthalapudi K; Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, USA. krishna.chinthalapudi@osumc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 07; Vol. 15 (1), pp. 9650. Date of Electronic Publication: 2024 Nov 07.
DOI: 10.1038/s41467-024-53773-6
Abstrakt: Plasma membrane repair in response to damage is essential for cell viability. The ferlin family protein dysferlin plays a key role in Ca 2+ -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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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