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Molecular Dynamics Simulations Elucidate the Molecular Basis of Pre-mRNA Translocation by the Prp2 Spliceosomal

Sefora Naomi Agrò1, Riccardo Rozza1, Santiago Movilla2

  • 1National Research Council of Italy (CNR)─Institute of Material (IOM) c/o International School for Advanced Studies (SISSA), Via Bonomea, 265, 34136 Trieste, Italy.

Journal of Chemical Information and Modeling
|June 28, 2023
PubMed

Insights

The spliceosome

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • The spliceosome is a large molecular machine that catalyzes pre-messenger RNA (pre-mRNA) splicing.
  • RNA-dependent ATPases/helicases are crucial for spliceosome remodeling.
  • Prp2, a DExH-box ATPase/helicase, is essential for spliceosome activation.

Purpose of the Study:

  • To elucidate the functional coupling between the ATPase and helicase activities of Prp2.
  • To understand the mechanism of pre-mRNA translocation by Prp2.
  • To investigate the role of Prp2's C-terminal domain rotation in spliceosome remodeling.

Main Methods:

  • Multi-microsecond molecular dynamics simulations.
  • Analysis of protein-RNA interactions.
  • Investigating ATP binding, hydrolysis, and dissociation effects.

Main Results:

  • Established functional coupling between Prp2's ATPase and helicase activities.
  • Revealed a typewriter-like rotation of Prp2's C-terminal domain.
  • Demonstrated that this rotation, driven by specific residue interactions with pre-mRNA, facilitates translocation.

Conclusions:

  • Prp2-mediated pre-mRNA translocation is driven by ATP-dependent C-terminal domain rotation.
  • This mechanism is conserved among DExH-box helicases, suggesting a general principle for RNA translocation.

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