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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Padrick SB,Cheng HC,Ismail AM,Panchal SC,Doolittle LK,Kim S,Skehan BM,Umetani J,Brautigam CA,Leong JM,Rosen MKdoi
10.1016/j.molcel.2008.10.012subject
Has Abstractpub_date
2008-11-07 00:00:00pages
426-38issue
3eissn
1097-2765issn
1097-4164pii
S1097-2765(08)00726-0journal_volume
32pub_type
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