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 language | English (US) |
---|---|
Pages (from-to) | 426-438 |
Number of pages | 13 |
Journal | Molecular cell |
Volume | 32 |
Issue number | 3 |
DOIs | |
State | Published - Nov 7 2008 |
Keywords
- CELLBIO
- PROTEINS
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology