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

Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):E5552-61. doi: 10.1073/pnas.1524412113. Epub 2016 Sep 6.


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.

Keywords: Drosophila; F-BAR; Nwk; WASp; actin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Drosophila
  • Drosophila Proteins / chemistry*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Humans
  • Ligands
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Protein Binding
  • Wiskott-Aldrich Syndrome Protein, Neuronal / chemistry*
  • Wiskott-Aldrich Syndrome Protein, Neuronal / genetics
  • src Homology Domains / genetics


  • Drosophila Proteins
  • Ligands
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Wiskott-Aldrich Syndrome Protein, Neuronal
  • nwk protein, Drosophila