Structural basis for regulation of Arp2/3 complex by GMF

Area of Science:

• Cell Biology
• Structural Biology
• Biochemistry

Background:

• The Arp2/3 complex is essential for forming cellular structures like lamellipodia through actin filament nucleation.
• Over a dozen regulators control Arp2/3 complex activity, but the structural basis of their interaction remains unclear.
• Gelsolin-like?’” motif-containing protein (GMF) is a regulator that inhibits nucleation and disassembles actin branches.

Purpose of the Study:

• To elucidate the structural mechanism by which GMF interacts with and regulates the Arp2/3 complex.
• To understand how GMF inhibits Arp2/3 complex nucleation and promotes branch disassembly.

Main Methods:

• Determined the crystal structure of the 240-kDa complex formed by Mus musculus GMF and Bos taurus Arp2/3 complex.
• Utilized structural analysis to identify the binding interface between GMF and the Arp2/3 complex.

Main Results:

• GMF binds to the barbed end of Arp2, a site overlapping with the proposed binding region for WASP-family proteins.
• The GMF-Arp2/3 complex structure suggests a cofilin-like mechanism for actin branch disassembly.
• The GMF ADF-H actin-binding domain specifically recognizes the Arp2/3 complex, not actin filaments.

Conclusions:

• GMF binding to Arp2 directly inhibits Arp2/3 complex-mediated actin nucleation.
• GMF likely disassembles actin branches via a modified cofilin-like mechanism.
• The ADF-H domain's specificity for the Arp2/3 complex is key to GMF's regulatory function.