F- and G-actin homeostasis regulates mechanosensitive actin nucleation by formins

2013 ◽  
Vol 15 (4) ◽  
pp. 395-405 ◽  
Author(s):  
Chiharu Higashida ◽  
Tai Kiuchi ◽  
Yushi Akiba ◽  
Hiroaki Mizuno ◽  
Masahiro Maruoka ◽  
...  
Keyword(s):  
Actin Nucleation ◽  
Actin Homeostasis

scholarly journals Mechanism of N-Wasp Activation by Cdc42 and Phosphatidylinositol 4,5-Bisphosphate

2000 ◽  
Vol 150 (6) ◽  
pp. 1299-1310 ◽  
Author(s):  
Rajat Rohatgi ◽  
Hsin-yi Henry Ho ◽  
Marc W. Kirschner
Keyword(s):  
Binding Site ◽  
Physical Interaction ◽  
Regulatory Interaction ◽  
Actin Nucleation ◽  
Sequence Element ◽  
Effector Domain ◽  
Nucleation Activity ◽  
Syndrome Protein ◽  
Upstream Regulators ◽  
Terminal Effector

Neuronal Wiskott-Aldrich Syndrome protein (N-WASP) transmits signals from Cdc42 to the nucleation of actin filaments by Arp2/3 complex. Although full-length N-WASP is a weak activator of Arp2/3 complex, its activity can be enhanced by upstream regulators such as Cdc42 and PI(4,5)P2. We dissected this activation reaction and found that the previously described physical interaction between the NH2-terminal domain and the COOH-terminal effector domain of N-WASP is a regulatory interaction because it can inhibit the actin nucleation activity of the effector domain by occluding the Arp2/3 binding site. This interaction between the NH2- and COOH termini must be intramolecular because in solution N-WASP is a monomer. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) influences the activity of N-WASP through a conserved basic sequence element located near the Cdc42 binding site rather than through the WASp homology domain 1. Like Cdc42, PI(4,5)P2 reduces the affinity between the NH2- and COOH termini of the molecule. The use of a mutant N-WASP molecule lacking this basic stretch allowed us to delineate a signaling pathway in Xenopus extracts leading from PI(4,5)P2 to actin nucleation through Cdc42, N-WASP, and Arp2/3 complex. In this pathway, PI(4,5)P2 serves two functions: first, as an activator of N-WASP; and second, as an indirect activator of Cdc42.

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