Hierarchical regulation of WASP/WAVE proteins
Department of Molecular Genetics and Microbiology
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.
DOI of Published Version
Mol Cell. 2008 Nov 7;32(3):426-38. Link to article on publisher's site
Padrick SB, Cheng H, 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. GSBS Student Publications. https://doi.org/10.1016/j.molcel.2008.10.012. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1607