Coordinated autoinhibition of F-BAR domain membrane binding and WASp activation by Nervous Wreck

Abstract

Membrane remodeling by Fes/Cip4 homology-Bin/Amphiphysin/Rvs167 (F-BAR) proteins is regulated by autoinhibitory interactions between their SRC homology 3 (SH3) and F-BAR domains. The structural basis of autoregulation, and whether it affects interactions of SH3 domains with other cellular ligands, remain unclear. Here we used single-particle electron microscopy to determine the structure of the F-BAR protein Nervous Wreck (Nwk) in both soluble and membrane-bound states. On membrane binding, Nwk SH3 domains do not completely dissociate from the F-BAR dimer, but instead shift from its concave surface to positions on either side of the dimer. Unexpectedly, along with controlling membrane binding, these autoregulatory interactions inhibit the ability of Nwk-SH3a to activate Wiskott–Aldrich syndrome protein (WASp)/actin related protein (Arp) 2/3-dependent actin filament assembly. In Drosophila neurons, Nwk autoregulation restricts SH3a domain-dependent synaptopod formation, synaptic growth, and actin organization. Our results define structural rearrangements in Nwk that control F-BAR–membrane interactions as well as SH3 domain activities, and suggest that these two functions are tightly coordinated in vitro and in vivo.

Regulation of the interaction between the neuronal BIN1 isoform 1 and Tau proteins – role of the SH3 domain

“…Interactions of amphiphysin-related proteins are regulated by complex mechanisms, not yet fully understood. Previous reports showed in amphiphysin-related proteins that intramolecular interaction of a C-terminal SH3 domain is able to modulate interactions with membranes and/or molecular partners [25][26][27][28][29][30]. A possible reason for the reduced mobility of BIN1-SH3 domain in the context of BIN1Iso1 could be its involvement in such an intramolecular interaction.…”

“…Previous reports showed in amphiphysin-related proteins that intramolecular interaction of a C-terminal SH3 domain is able to modulate interactions with membranes and/or molecular partners [25][26][27][28][29][30]. Previous reports showed in amphiphysin-related proteins that intramolecular interaction of a C-terminal SH3 domain is able to modulate interactions with membranes and/or molecular partners [25][26][27][28][29][30].…”

Receptor‐Free Signaling at Curved Cellular Membranes

“…Furthermore, a number of BAR domain proteins carry Src-homology 3 (SH3) or Wiskott-Aldrich syndrome protein (WASP) homology 2 (WH2) domains. [45] Furthermore, the system shows nonlinearity, whereby individual components casually influence each other in a positive manner (i.e., positive feedback). These findings are relevant, as they posit the existence of autoregulatory modules that control actin dynamics at deforming membranes.…”

“…[45] Hence, great caution should be exercised when interpreting such experimental data. For example, membrane charge has been described to modulate binding orientations of BAR domains to the bilayer, or release autoinhibition of individual domains within BAR proteins.…”

Effects of PI(4,5)P2 concentration on the F‐BAR domain membrane binding as revealed by coarse‐grained simulations

“…Nwk functions in the Drosophila neuromuscular junction and contains one F‐BAR and two SH3 domains that modulate the F‐BAR's activity and are also responsible for interactions with WASp and other proteins engaged in actin dynamics . In contrast to other F‐BAR domains, the F‐BAR domain of Nwk does not tubulate membranes of liposomes, but causes the formation of ridges and scallops .…”