Hierarchical regulation of WASP/WAVE proteins

Mol Cell. 2008 Nov 7;32(3):426-38. doi: 10.1016/j.molcel.2008.10.012.

Abstract

Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Allosteric Regulation
  • Binding Sites
  • Cell Membrane / metabolism
  • Dimerization
  • Homeostasis
  • Humans
  • Image Processing, Computer-Assisted
  • Kinetics
  • Protein Conformation
  • Protein Folding
  • Wiskott-Aldrich Syndrome / genetics*
  • Wiskott-Aldrich Syndrome / metabolism*
  • Wiskott-Aldrich Syndrome Protein / genetics*
  • Wiskott-Aldrich Syndrome Protein / metabolism*
  • Wiskott-Aldrich Syndrome Protein Family / chemistry
  • Wiskott-Aldrich Syndrome Protein Family / genetics*
  • Wiskott-Aldrich Syndrome Protein Family / metabolism*

Substances

  • Actins
  • WASF1 protein, human
  • Wiskott-Aldrich Syndrome Protein
  • Wiskott-Aldrich Syndrome Protein Family