Structural basis of actin filament assembly and aging

Area of Science:

• Biochemistry
• Structural Biology
• Cell Biology

Background:

• Actin filament (F-actin) turnover is crucial for eukaryotic cellular motility.
• The precise mechanisms of F-actin ATP hydrolysis, conformational changes, and depolymerization remain incompletely understood.

Purpose of the Study:

• To elucidate the structural basis of actin filament nucleotide states and polymerization dynamics.
• To understand the role of water molecules and inorganic phosphate release in F-actin assembly and aging.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at approximately 2.2 Å resolution.
• Structural analysis of F-actin in various nucleotide states with Mg²⁺ or Ca²⁺.

Main Results:

• Actin polymerization relocates water molecules, activating ATP hydrolysis.
• Inorganic phosphate release is transient, with closed pathways observed in all structures.
• Subtle nucleotide-binding pocket changes are amplified and transmitted to the filament periphery.
• Differences in water positions explain varied polymerization rates between Ca²⁺-actin and Mg²⁺-actin.

Conclusions:

• Solvent-driven rearrangements govern actin filament assembly and aging.
• The findings provide a structural foundation for designing F-actin-targeting drugs for imaging and therapeutics.