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Monovalent metal ion binding promotes the first transesterification reaction in the spliceosome

Author

Listed:
  • Jana Aupič

    (National Research Council of Italy (CNR)—Materials Foundry (IOM) c/o International School for Advanced Studies (SISSA))

  • Jure Borišek

    (National Institute of Chemistry)

  • Sebastian M. Fica

    (University of Oxford)

  • Wojciech P. Galej

    (European Molecular Biology Laboratory)

  • Alessandra Magistrato

    (National Research Council of Italy (CNR)—Materials Foundry (IOM) c/o International School for Advanced Studies (SISSA))

Abstract

Cleavage and formation of phosphodiester bonds in nucleic acids is accomplished by large cellular machineries composed of both protein and RNA. Long thought to rely on a two-metal-ion mechanism for catalysis, structure comparisons revealed many contain highly spatially conserved second-shell monovalent cations, whose precise function remains elusive. A recent high-resolution structure of the spliceosome, essential for pre-mRNA splicing in eukaryotes, revealed a potassium ion in the active site. Here, we employ biased quantum mechanics/ molecular mechanics molecular dynamics to elucidate the function of this monovalent ion in splicing. We discover that the K+ ion regulates the kinetics and thermodynamics of the first splicing step by rigidifying the active site and stabilizing the substrate in the pre- and post-catalytic state via formation of key hydrogen bonds. Our work supports a direct role for the K+ ion during catalysis and provides a mechanistic hypothesis likely shared by other nucleic acid processing enzymes.

Suggested Citation

  • Jana Aupič & Jure Borišek & Sebastian M. Fica & Wojciech P. Galej & Alessandra Magistrato, 2023. "Monovalent metal ion binding promotes the first transesterification reaction in the spliceosome," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44174-2
    DOI: 10.1038/s41467-023-44174-2
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    References listed on IDEAS

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    1. Sebastian M. Fica & Nicole Tuttle & Thaddeus Novak & Nan-Sheng Li & Jun Lu & Prakash Koodathingal & Qing Dai & Jonathan P. Staley & Joseph A. Piccirilli, 2013. "RNA catalyses nuclear pre-mRNA splicing," Nature, Nature, vol. 503(7475), pages 229-234, November.
    2. Jacopo Manigrasso & Isabel Chillón & Vito Genna & Pietro Vidossich & Srinivas Somarowthu & Anna Marie Pyle & Marco De Vivo & Marco Marcia, 2020. "Visualizing group II intron dynamics between the first and second steps of splicing," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Alexey Rozov & Iskander Khusainov & Kamel El Omari & Ramona Duman & Vitaliy Mykhaylyk & Marat Yusupov & Eric Westhof & Armin Wagner & Gulnara Yusupova, 2019. "Importance of potassium ions for ribosome structure and function revealed by long-wavelength X-ray diffraction," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Wojciech P. Galej & Max E. Wilkinson & Sebastian M. Fica & Chris Oubridge & Andrew J. Newman & Kiyoshi Nagai, 2016. "Cryo-EM structure of the spliceosome immediately after branching," Nature, Nature, vol. 537(7619), pages 197-201, September.
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