Abstract
Synaptic membrane-remodeling events such as endocytosis require force-generating actin assembly. The endocytic machinery that regulates these actin and membrane dynamics localizes at high concentrations to large areas of the presynaptic membrane, but actin assembly and productive endocytosis are far more restricted in space and time. Here we describe a mechanism whereby autoinhibition clamps the presynaptic endocytic machinery to limit actin assembly to discrete functional events. We found that collective interactions between the Drosophila endocytic proteins Nwk/FCHSD2, Dap160/intersectin, and WASp relieve Nwk autoinhibition and promote robust membrane-coupled actin assembly in vitro. Using automated particle tracking to quantify synaptic actin dynamics in vivo, we discovered that Nwk-Dap160 interactions constrain spurious assembly of WASp-dependent actin structures. These interactions also promote synaptic endocytosis, suggesting that autoinhibition both clamps and primes the synaptic endocytic machinery, thereby constraining actin assembly to drive productive membrane remodeling in response to physiological cues.
Highlights
At neuronal presynaptic terminals, actin assembly affects many physiological processes including synapse morphogenesis, traffic of numerous vesicular cargoes, and synaptic vesicle endocytosis, organization, and mobility (Dillon and Goda, 2005; Nelson et al, 2013; Papandreou and Leterrier, 2018)
We have identified a mechanism by which autoinhibition clamps the presynaptic endocytic machinery to regulate the dynamics of discrete synaptic actin assembly events and the efficiency of synaptic endocytosis
Our data suggest a model in which specific interactions among Nervous Wreck (Nwk), Dap160, and WASp function in two ways to potentiate membrane-associated actin dynamics
Summary
Actin assembly affects many physiological processes including synapse morphogenesis, traffic of numerous vesicular cargoes, and synaptic vesicle endocytosis, organization, and mobility (Dillon and Goda, 2005; Nelson et al, 2013; Papandreou and Leterrier, 2018). Presynaptic terminals maintain constitutively high local concentrations of actin-associated endocytic regulatory proteins at synaptic membranes (Reshetniak et al, 2020; Wilhelm et al, 2014), yet only a small fraction of this protein pool is likely to be active at any point in time (in response to vesicle release) and space (at
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
