Structural insights into lipid membrane binding by human ferlins.
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ICR Authors
Authors
Cretu, C
Chernev, A
Kibédi Szabó, CZ
Pena, V
Urlaub, H
Moser, T
Preobraschenski, J
Chernev, A
Kibédi Szabó, CZ
Pena, V
Urlaub, H
Moser, T
Preobraschenski, J
Document Type
Journal Article
Date
2025-07-15
Date Accepted
2025-04-25
Abstract
Ferlins are ancient membrane proteins with a unique architecture, and play central roles in crucial processes that involve Ca2+-dependent vesicle fusion. Despite their links to multiple human diseases and numerous functional studies, a mechanistic understanding of how these multi-C2 domain-containing proteins interact with lipid membranes to promote membrane remodelling and fusion is currently lacking. Here we obtain near-complete cryo-electron microscopy structures of human myoferlin and dysferlin in their Ca2+- and lipid-bound states. We show that ferlins adopt compact, ring-like tertiary structures upon membrane binding. The top arch of the ferlin ring, composed of the C2C-C2D region, is rigid and exhibits only little variability across the observed functional states. In contrast, the N-terminal C2B and the C-terminal C2F-C2G domains cycle between alternative conformations and, in response to Ca2+, close the ferlin ring, promoting tight interaction with the target membrane. Probing key domain interfaces validates the observed architecture, and informs a model of how ferlins engage lipid bilayers in a Ca2+-dependent manner. This work reveals the general principles of human ferlin structures and provides a framework for future analyses of ferlin-dependent cellular functions and disease mechanisms.
Citation
EMBO Journal, 2025, 44 (14), pp. 3926 - 3958
Source Title
EMBO Journal
Publisher
SPRINGERNATURE
ISSN
0261-4189
eISSN
1460-2075
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Research Team
Mech of pre-mRNA splicing