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bioRxiv · 10.64898/2025.12.01.691618

Structural mechanisms of drebrin-mediated F-actin network modulation

Zhao, W.·Abis, G.·Oozeer, F.·Mulvaney, T.·Nagar, N.·Topf, M.·Gordon-Weeks, P. R.·Conte, M. R.·Atherton, J.
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Abstract

Drebrin modulates F-actin networks and links them to other intracellular components, regulating crucial processes including neuritogenesis, synaptic plasticity, virus internalisation and cancer invasion. Using single-particle cryo-EM we characterise drebrins interaction with F-actin through two separate conserved actin binding domains (ABD1 and ABD2), revealing structural bases for its F-actin-modulating properties. We describe a multimodal interaction where drebrins ABD1 can adopt two conformations and a long flexible loop connecting to ABD2 allows the two ABDs to occupy multiple relative positions along F-actin. Despite harbouring two separated ABDs, we find that drebrin is not a strong direct F-actin bundler. Drebrins ABDs bind across multiple actin protomers and their subdomains and modify the longitudinal inter-protomer interface, explaining their F-actin stabilising properties. Furthermore, we show drebrins binding site on F-actin is shared with other critical actin-binding and regulatory proteins, explaining their competitive displacement.

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Zhao, W., Abis, G., Oozeer, F., Mulvaney, T., Nagar, N., Topf, M., Gordon-Weeks, P. R., Conte, M. R., Atherton, J.. 2025-12-02. Structural mechanisms of drebrin-mediated F-actin network modulation. https://doi.org/10.64898/2025.12.01.691618

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