Structural basis of actin filament assembly and aging

Article

关键词: CRYO-EM STRUCTURE;    BOUND DIVALENT-CATION;    BEAM-INDUCED MOTION;    ATP HYDROLYSIS;    F-ACTIN;    BAYESIAN-APPROACH;    BINDING;    MECHANISM;    DYNAMICS;    ADF/COFILIN;   

DOI  :  10.1038/s41586-022-05241-8

来源: SCIE

【 摘 要 】

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 angstrom 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.

【 授权许可】

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