Molecular mechanisms of inorganic-phosphate release from the core and barbed end of actin filaments.

Autor: Oosterheert W; Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany., Blanc FEC; Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany., Roy A; Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany., Belyy A; Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany., Sanders MB; Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany., Hofnagel O; Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany., Hummer G; Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany. gerhard.hummer@biophys.mpg.de.; Institute for Biophysics, Goethe University, Frankfurt am Main, Germany. gerhard.hummer@biophys.mpg.de., Bieling P; Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany. peter.bieling@mpi-dortmund.mpg.de., Raunser S; Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany. stefan.raunser@mpi-dortmund.mpg.de.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2023 Nov; Vol. 30 (11), pp. 1774-1785. Date of Electronic Publication: 2023 Sep 25.
DOI: 10.1038/s41594-023-01101-9
Abstrakt: The release of inorganic phosphate (P i ) from actin filaments constitutes a key step in their regulated turnover, which is fundamental to many cellular functions. The mechanisms underlying P i release from the core and barbed end of actin filaments remain unclear. Here, using human and bovine actin isoforms, we combine cryo-EM with molecular-dynamics simulations and in vitro reconstitution to demonstrate how actin releases P i through a 'molecular backdoor'. While constantly open at the barbed end, the backdoor is predominantly closed in filament-core subunits and opens only transiently through concerted amino acid rearrangements. This explains why P i escapes rapidly from the filament end but slowly from internal subunits. In a nemaline-myopathy-associated actin variant, the backdoor is predominantly open in filament-core subunits, resulting in accelerated P i release and filaments with drastically shortened ADP-P i caps. Our results provide the molecular basis for P i release from actin and exemplify how a disease-linked mutation distorts the nucleotide-state distribution and atomic structure of the filament.
(© 2023. The Author(s).)
Databáze: MEDLINE
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