Mechanism of phosphate release from actin filaments.
Proc Natl Acad Sci U S A
; 121(29): e2408156121, 2024 Jul 16.
Article
em En
| MEDLINE
| ID: mdl-38980907
ABSTRACT
After ATP-actin monomers assemble filaments, the ATP's [Formula see text]-phosphate is hydrolyzedwithin seconds and dissociates over minutes. We used all-atom molecular dynamics simulations to sample the release of phosphate from filaments and study residues that gate release. Dissociation of phosphate from Mg2+ is rate limiting and associated with an energy barrier of 20 kcal/mol, consistent with experimental rates of phosphate release. Phosphate then diffuses within an internal cavity toward a gate formed by R177, as suggested in prior computational studies and cryo-EM structures. The gate is closed when R177 hydrogen bonds with N111 and is open when R177 forms a salt bridge with D179. Most of the time, interactions of R177 with other residues occlude the phosphate release pathway. Machine learning analysis reveals that the occluding interactions fluctuate rapidly, underscoring the secondary role of backdoor gate opening in Pi release, in contrast with the previous hypothesis that gate opening is the primary event.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfatos
/
Citoesqueleto de Actina
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Trifosfato de Adenosina
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Simulação de Dinâmica Molecular
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article