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

136 Citations (Scopus)

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

Fingerprint

Wiskott-Aldrich Syndrome Protein Family
Wiskott-Aldrich Syndrome Protein
Actins
Actin-Related Protein 2-3 Complex
Dimerization
Allosteric Regulation
src Homology Domains
Eukaryotic Cells
Cluster Analysis
Membranes

Keywords

  • CELLBIO
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Padrick, S. B., Cheng, H. C., Ismail, A. M., Panchal, S. C., Doolittle, L. K., Kim, S., ... 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

Hierarchical Regulation of WASP/WAVE Proteins. / Padrick, Shae B.; Cheng, Hui Chun; Ismail, Ayman M.; Panchal, Sanjay C.; Doolittle, Lynda K.; Kim, Soyeon; Skehan, Brian M.; Umetani, Junko; Brautigam, Chad A; Leong, John M.; Rosen, Michael K.

In: Molecular Cell, Vol. 32, No. 3, 07.11.2008, p. 426-438.

Research output: Contribution to journalArticle

Padrick, SB, Cheng, HC, Ismail, AM, Panchal, SC, Doolittle, LK, Kim, S, Skehan, BM, Umetani, J, Brautigam, CA, Leong, JM & Rosen, MK 2008, 'Hierarchical Regulation of WASP/WAVE Proteins', Molecular Cell, vol. 32, no. 3, pp. 426-438. https://doi.org/10.1016/j.molcel.2008.10.012
Padrick SB, Cheng HC, Ismail AM, Panchal SC, Doolittle LK, Kim S et al. Hierarchical Regulation of WASP/WAVE Proteins. Molecular Cell. 2008 Nov 7;32(3):426-438. https://doi.org/10.1016/j.molcel.2008.10.012
Padrick, Shae B. ; Cheng, Hui Chun ; Ismail, Ayman M. ; Panchal, Sanjay C. ; Doolittle, Lynda K. ; Kim, Soyeon ; Skehan, Brian M. ; Umetani, Junko ; Brautigam, Chad A ; Leong, John M. ; Rosen, Michael K. / Hierarchical Regulation of WASP/WAVE Proteins. In: Molecular Cell. 2008 ; Vol. 32, No. 3. pp. 426-438.
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