Hierarchical regulation of WASP/WAVE proteins
Department of Molecular Genetics and Microbiology
Medical Subject Headings
Actins; Allosteric Regulation; Binding Sites; Cell Membrane; Dimerization; Homeostasis; Humans; Image Processing, Computer-Assisted; Kinetics; Protein Conformation; Protein Folding; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein Family
Life Sciences | Medicine and Health Sciences
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.
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Citation: Mol Cell. 2008 Nov 7;32(3):426-38. Link to article on publisher's site
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.; and Rosen, Michael K., "Hierarchical regulation of WASP/WAVE proteins" (2008). GSBS Student Publications. 1607.