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RNA recognition by Npl3p reveals U2 snRNA-binding compatible with a chaperone role during splicing

Author

Listed:
  • Ahmed Moursy

    (Institute of Biochemistry
    Novartis Institutes for BioMedical Research)

  • Antoine Cléry

    (Institute of Biochemistry)

  • Stefan Gerhardy

    (Institute of Biochemistry
    University of Zurich
    Sardona Therapeutics)

  • Katharina M. Betz

    (University of Zurich)

  • Sanjana Rao

    (University of Zurich)

  • Jarosław Mazur

    (University of Zurich)

  • Sébastien Campagne

    (Institute of Biochemistry
    University of Bordeaux)

  • Irene Beusch

    (Institute of Biochemistry
    University of California, San Francisco)

  • Malgorzata M. Duszczyk

    (Institute of Biochemistry)

  • Mark D. Robinson

    (University of Zurich)

  • Vikram Govind Panse

    (University of Zurich
    University of Zurich)

  • Frédéric H.-T. Allain

    (Institute of Biochemistry)

Abstract

The conserved SR-like protein Npl3 promotes splicing of diverse pre-mRNAs. However, the RNA sequence(s) recognized by the RNA Recognition Motifs (RRM1 & RRM2) of Npl3 during the splicing reaction remain elusive. Here, we developed a split-iCRAC approach in yeast to uncover the consensus sequence bound to each RRM. High-resolution NMR structures show that RRM2 recognizes a 5´-GNGG-3´ motif leading to an unusual mille-feuille topology. These structures also reveal how RRM1 preferentially interacts with a CC-dinucleotide upstream of this motif, and how the inter-RRM linker and the region C-terminal to RRM2 contribute to cooperative RNA-binding. Structure-guided functional studies show that Npl3 genetically interacts with U2 snRNP specific factors and we provide evidence that Npl3 melts U2 snRNA stem-loop I, a prerequisite for U2/U6 duplex formation within the catalytic center of the Bact spliceosomal complex. Thus, our findings suggest an unanticipated RNA chaperoning role for Npl3 during spliceosome active site formation.

Suggested Citation

  • Ahmed Moursy & Antoine Cléry & Stefan Gerhardy & Katharina M. Betz & Sanjana Rao & Jarosław Mazur & Sébastien Campagne & Irene Beusch & Malgorzata M. Duszczyk & Mark D. Robinson & Vikram Govind Panse , 2023. "RNA recognition by Npl3p reveals U2 snRNA-binding compatible with a chaperone role during splicing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42962-4
    DOI: 10.1038/s41467-023-42962-4
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    References listed on IDEAS

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    1. Fu-Lung Yeh & Shang-Lin Chang & Golam Rizvee Ahmed & Hsin-I Liu & Luh Tung & Chung-Shu Yeh & Leah Stands Lanier & Corina Maeder & Che-Min Lin & Shu-Chun Tsai & Wan-Yi Hsiao & Wei-Hau Chang & Tien-Hsie, 2021. "Activation of Prp28 ATPase by phosphorylated Npl3 at a critical step of spliceosome remodeling," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Gesa Zander & Alexandra Hackmann & Lysann Bender & Daniel Becker & Thomas Lingner & Gabriela Salinas & Heike Krebber, 2016. "mRNA quality control is bypassed for immediate export of stress-responsive transcripts," Nature, Nature, vol. 540(7634), pages 593-596, December.
    3. Daniel Jutzi & Sébastien Campagne & Ralf Schmidt & Stefan Reber & Jonas Mechtersheimer & Foivos Gypas & Christoph Schweingruber & Martino Colombo & Christine Schroetter & Fionna E. Loughlin & Anny Dev, 2020. "Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced amyotrophic lateral sclerosis," Nature Communications, Nature, vol. 11(1), pages 1-14, 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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