Molecular Dynamics Simulations Elucidate the Molecular Basis of Pre-mRNA Translocation by the Prp2 Spliceosomal Helicase
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https://doi.org/10.1021/acs.jcim.3c00585 |
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Título
Molecular Dynamics Simulations Elucidate the Molecular Basis of Pre-mRNA Translocation by the Prp2 Spliceosomal HelicaseAutoría
Fecha de publicación
2023-06-28Editor
American Chemical SocietyCita bibliográfica
AGRÒ, Sefora Naomi, et al. Molecular Dynamics Simulations Elucidate the Molecular Basis of Pre-mRNA Translocation by the Prp2 Spliceosomal Helicase. Journal of Chemical Information and Modeling, 2023, vol. 63, no 13, p. 4180-4189.Tipo de documento
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info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
The spliceosome machinery catalyzes precursor-messenger RNA (pre-mRNA) splicing by undergoing at each splicing cycle assembly, activation, catalysis, and disassembly processes, thanks to the concerted action of specific ... [+]
The spliceosome machinery catalyzes precursor-messenger RNA (pre-mRNA) splicing by undergoing at each splicing cycle assembly, activation, catalysis, and disassembly processes, thanks to the concerted action of specific RNA-dependent ATPases/helicases. Prp2, a member of the DExH-box ATPase/helicase family, harnesses the energy of ATP hydrolysis to translocate a single pre-mRNA strand in the 5′ to 3′ direction, thus promoting spliceosome remodeling to its catalytic-competent state. Here, we established the functional coupling between ATPase and helicase activities of Prp2. Namely, extensive multi-μs molecular dynamics simulations allowed us to unlock how, after pre-mRNA selection, ATP binding, hydrolysis, and dissociation induce a functional typewriter-like rotation of the Prp2 C-terminal domain. This movement, endorsed by an iterative swing of interactions established between specific Prp2 residues with the nucleobases at 5′- and 3′-ends of pre-mRNA, promotes pre-mRNA translocation. Notably, some of these Prp2 residues are conserved in the DExH-box family, suggesting that the translocation mechanism elucidated here may be applicable to all DExH-box helicases. [-]
Entidad financiadora
Italian Association for Cancer Research (AIRC) | Piano Nazionale di Ripresa e Resilienza (PNRR) | National Center for Gene Therapy and Drugs based on RNA Technology, Italia
Código del proyecto o subvención
IG grant 24514 | CUP B83C22002860006 CN_0000004 | “Giovanni Fraviga” fellowship
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Copyright © 2023 American Chemical Society
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