Structure and control of the actin regulatory WAVE complex

Area of Science:

• Cell biology
• Molecular biology
• Biochemistry

Background:

• The Wiskott-Aldrich syndrome protein (WASP) family regulates cytoskeletal dynamics.
• WASP relative WAVE, within the WAVE regulatory complex (WRC), controls lamellipodia formation.
• WRC is typically inactive towards the Arp2/3 complex but can be stimulated by Rac GTPase, kinases, and phosphatidylinositols.

Purpose of the Study:

• To determine the crystal structure of the WRC.
• To elucidate the mechanism of WRC activation by Rac GTPase, kinases, and phospholipids.
• To understand how WRC regulates actin nucleation via the Arp2/3 complex.

Main Methods:

• X-ray crystallography (2.3-ångstrom resolution)
• Biochemical assays
• Mechanistic analyses

Main Results:

• The crystal structure reveals that the WAVE Verprolin homology, Cofilins homology, and Acidic (VCA) motif is sequestered within the WRC.
• Rac GTPase and kinases destabilize a key WRC element responsible for VCA sequestration, thereby activating the complex.
• The WRC structure suggests cooperative recruitment to membranes by Rac GTPase and phospholipids.

Conclusions:

• The WRC structure provides insights into the regulation of actin nucleation by the WAVE protein.
• Rac GTPase, kinases, and phospholipids act synergistically to control WRC activity and localization.
• Understanding WRC regulation is crucial for comprehending cell migration and cytoskeletal dynamics.