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bioRxiv · 10.1101/2025.01.25.634844

Structural Basis of Lipid Membrane Binding by Human Ferlins

Cretu, C.·Chernev, A.·Szabo, C. Z. K.·Pena, V.·Urlaub, H.·Moser, T.·Preobraschenski, J.
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Abstract

Ferlins, ancient membrane proteins with a unique architecture, are central to multiple essential, Ca2+-dependent vesicle fusion processes. Despite numerous functional studies and their link to burdening human diseases, a mechanistic understanding of how these multi-C2 domain proteins interact with lipid membranes to promote their remodeling and fusion is currently lacking. Here, we elucidate the 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 achieved upon membrane binding. The top arch of the ferlin ring, comprising the C2C-C2D region, is rigid and varies little 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.

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Cretu, C., Chernev, A., Szabo, C. Z. K., Pena, V., Urlaub, H., Moser, T., Preobraschenski, J.. 2025-01-27. Structural Basis of Lipid Membrane Binding by Human Ferlins. https://doi.org/10.1101/2025.01.25.634844

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