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Publication Abstract from PubMed

The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state^1-3. It remains unclear how F-actin hydrolyses ATP and subsequently undergoes subtle conformational rearrangements that ultimately lead to filament depolymerization by actin-binding proteins. Here we present cryo-electron microscopy structures of F-actin in all nucleotide states, polymerized in the presence of Mg²⁺ or Ca²⁺ at approximately 2.2 A resolution. The structures show that actin polymerization induces the relocation of water molecules in the nucleotide-binding pocket, activating one of them for the nucleophilic attack of ATP. Unexpectedly, the back door for the subsequent release of inorganic phosphate (P_i) is closed in all structures, indicating that P_i release occurs transiently. The small changes in the nucleotide-binding pocket after ATP hydrolysis and P_i release are sensed by a key amino acid, amplified and transmitted to the filament periphery. Furthermore, differences in the positions of water molecules in the nucleotide-binding pocket explain why Ca²⁺-actin shows slower polymerization rates than Mg²⁺-actin. Our work elucidates the solvent-driven rearrangements that govern actin filament assembly and aging and lays the foundation for the rational design of drugs and small molecules for imaging and therapeutic applications.

Structural basis of actin filament assembly and aging.,Oosterheert W, Klink BU, Belyy A, Pospich S, Raunser S Nature. 2022 Nov;611(7935):374-379. doi: 10.1038/s41586-022-05241-8. Epub 2022, Oct 26. PMID:36289337^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.