Abstract
F-BAR domain proteins regulate and sense membrane curvature by interacting with negatively charged phospholipids and assembling into higher-order scaffolds. However, regulatory mechanisms controlling these interactions are poorly understood. Here, we show that Drosophila Nervous Wreck (Nwk) is autoregulated by a C-terminal SH3 domain module that interacts directly with its F-BAR domain. Surprisingly, this autoregulation does not mediate a simple “on-off” switch for membrane remodeling. Instead, the isolated Nwk F-BAR domain efficiently assembles into higher-order structures and deforms membranes only within a limited range of negative membrane charge, and autoregulation elevates this range. Thus, autoregulation could either reduce membrane binding or promote higher-order assembly, depending on local cellular membrane composition. Our findings uncover an unexpected mechanism by which lipid composition directs membrane remodeling.
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•Nwk F-BAR membrane binding is autoregulated by SH3 domains in vivo and in vitro•Nwk binds membrane in an active assembled state or an inactive unassembled state•High PIP2 inhibits F-BAR membrane bending and favors promiscuous binding•Autoregulation increases the charge needed for Nwk F-BAR membrane binding
Membrane dynamics are critical to many cellular processes, but the molecular mechanisms that regulate remodeling events are not well understood. Here, Kelley et al. demonstrate that for the F-BAR protein Nervous Wreck, intramolecular autoregulation and membrane charge work together to restrict remodeling to a limited range of lipid compositions.