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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.
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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.

Source

Mol Cell. 2008 Nov 7;32(3):426-38. Link to article on publisher's site

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10.1016/j.molcel.2008.10.012
PubMed ID
18995840
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