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      Visualizing group II intron dynamics between the first and second steps of splicing

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          Abstract

          Group II introns are ubiquitous self-splicing ribozymes and retrotransposable elements evolutionarily and chemically related to the eukaryotic spliceosome, with potential applications as gene-editing tools. Recent biochemical and structural data have captured the intron in multiple conformations at different stages of catalysis. Here, we employ enzymatic assays, X-ray crystallography, and molecular simulations to resolve the spatiotemporal location and function of conformational changes occurring between the first and the second step of splicing. We show that the first residue of the highly-conserved catalytic triad is protonated upon 5’-splice-site scission, promoting a reversible structural rearrangement of the active site (toggling). Protonation and active site dynamics induced by the first step of splicing facilitate the progression to the second step. Our insights into the mechanism of group II intron splicing parallels functional data on the spliceosome, thus reinforcing the notion that these evolutionarily-related molecular machines share the same enzymatic strategy.

          Abstract

          Group II introns are self-splicing ribozymes. Here, the authors employ enzymatic assay, X-ray crystallography and molecular dynamics simulations to show that protonation of the group II intron catalytic triad plays an important role for the transition from the first to the second step of splicing.

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              Some applications of the transition state method to the calculation of reaction velocities, especially in solution

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                Author and article information

                Contributors
                marco.devivo@iit.it
                mmarcia@embl.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                5 June 2020
                5 June 2020
                2020
                : 11
                : 2837
                Affiliations
                [1 ]ISNI 0000 0004 1764 2907, GRID grid.25786.3e, Laboratory of Molecular Modelling & Drug Discovery, , Istituto Italiano di Tecnologia, ; Via Morego 30, 16163 Genoa, Italy
                [2 ]ISNI 0000 0004 0638 528X, GRID grid.418923.5, European Molecular Biology Laboratory (EMBL) Grenoble, ; 71 Avenue des Martyrs, Grenoble, 38042 France
                [3 ]Department of Structural and Computational Biology, Institute for Research in Biomedicine (IRB), Parc Científic de Barcelona, C/ Baldiri Reixac 10-12, 08028 Barcelona, Spain
                [4 ]ISNI 0000 0001 2181 3113, GRID grid.166341.7, Department of Biochemistry & Molecular Biology, , Drexel University College of Medicine, ; Philadelphia, PA USA
                [5 ]Department of Molecular, Cellular and Developmental Biology, New Haven, CT 06511 USA
                [6 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Chemistry, , Yale University, ; New Haven, CT 06511 USA
                [7 ]ISNI 0000 0001 2167 1581, GRID grid.413575.1, Howard Hughes Medical Institute, ; Chevy Chase, MD 20815 USA
                Author information
                http://orcid.org/0000-0003-4076-8930
                http://orcid.org/0000-0002-3107-8738
                http://orcid.org/0000-0003-4022-5661
                http://orcid.org/0000-0003-2430-0713
                Article
                16741
                10.1038/s41467-020-16741-4
                7275048
                32503992
                1fb954d7-2658-4001-8730-cf19375c17ed
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 October 2019
                : 18 May 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000011, Howard Hughes Medical Institute (HHMI);
                Funded by: FundRef https://doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research);
                Award ID: IG 23679
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100013060, European Molecular Biology Laboratory (EMBL Heidelberg);
                Award ID: EMBL Grenoble
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001665, Agence Nationale de la Recherche (French National Research Agency);
                Award ID: ANR-15-CE11-0003-01
                Award ID: ANR-10-INSB-05-02
                Award ID: ANR-10-LABX-49-01
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003323, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (National Agency for AIDS Research);
                Award ID: ECTZ18552
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004097, Fondation ARC pour la Recherche sur le Cancer (ARC Foundation for Cancer Research);
                Award ID: PJA-20191209284
                Award Recipient :
                Funded by: Alliance nationale pour les sciences de la vie et de la santé (Aviesan) - ITMO Cancer: Instituts thématiques multiorganismes (ITMO)
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                rna,structural biology,computational biology and bioinformatics
                Uncategorized
                rna, structural biology, computational biology and bioinformatics

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