Fascin structural plasticity mediates flexible actin bundle construction

Area of Science:

• Biochemistry
• Structural Biology
• Cell Biology

Background:

• Fascin is a key actin-binding protein that cross-links actin filaments (F-actin) into bundles.
• These bundles are crucial for cellular structures like filopodia and stereocilia.
• Dysregulation of fascin contributes to cancer metastasis, making it a therapeutic target.

Purpose of the Study:

• To elucidate the F-actin cross-linking mechanisms of human fascin-1 at various scales.
• To understand how fascin-1 builds and regulates actin bundles.
• To investigate the structural basis for fascin inhibitor activity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET).
• Custom denoising algorithms and computational modeling.
• Structural analysis of fascin-actin cross-bridges and filament bundles.

Main Results:

• Determined the asymmetric F-actin binding conformation of fascin.
• Identified that the inhibitor G2 allosterically blocks this binding site.
• Revealed fascin's structural plasticity enables adaptation to varied F-actin orientations in bundles.
• Uncovered geometric rules governing fascin binding patterns and bundle size limitation.

Conclusions:

• Fascin utilizes nanoscale structural dynamics to construct and control micron-scale actin bundles.
• Understanding fascin's mechanism provides insights into its role in cell migration and metastasis.
• The structural findings support the development of fascin-based cancer therapeutics.