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 journalArticle

138 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)426-438
Number of pages13
JournalMolecular cell
Volume32
Issue number3
DOIs
StatePublished - Nov 7 2008

Keywords

  • CELLBIO
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Padrick, S. B., Cheng, H. C., Ismail, A. M., Panchal, S. C., Doolittle, L. K., Kim, S., Skehan, B. M., Umetani, J., Brautigam, C. A., Leong, J. M., & Rosen, M. K. (2008). Hierarchical Regulation of WASP/WAVE Proteins. Molecular cell, 32(3), 426-438. https://doi.org/10.1016/j.molcel.2008.10.012