Membrane Charge Directs the Outcome of F-BAR Domain Lipid Binding and Autoregulation

• 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

SummaryF-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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