Hierarchical Regulation of WASP/WAVE Proteins

Shae B. Padrick, Hui Chun Cheng, Ayman M. Ismail, Sanjay C. Panchal, Lynda K. Doolittle, Soyeon Kim, Brian M. Skehan, Junko Umetani, Chad A Brautigam, John M. Leong, Michael K Rosen

Research output: Contribution to journalArticlepeer-review

152 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)426-438
Number of pages13
JournalMolecular cell
Issue number3
StatePublished - Nov 7 2008



ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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