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

Jana Aupič, Jure Borišek, Sebastian M. Fica, Wojciech P. Galej and Alessandra Magistrato ()
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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)

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44174-2

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