Structural mechanisms of drebrin-mediated F-actin network modulation

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.