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Molecular architecture of the human 17S U2 snRNP

Author

Listed:
  • Zhenwei Zhang

    (MPI for Biophysical Chemistry)

  • Cindy L. Will

    (MPI for Biophysical Chemistry)

  • Karl Bertram

    (MPI for Biophysical Chemistry)

  • Olexandr Dybkov

    (MPI for Biophysical Chemistry)

  • Klaus Hartmuth

    (MPI for Biophysical Chemistry)

  • Dmitry E. Agafonov

    (MPI for Biophysical Chemistry)

  • Romina Hofele

    (MPI for Biophysical Chemistry
    AstraZeneca)

  • Henning Urlaub

    (MPI for Biophysical Chemistry
    University Medical Center Göttingen)

  • Berthold Kastner

    (MPI for Biophysical Chemistry)

  • Reinhard Lührmann

    (MPI for Biophysical Chemistry)

  • Holger Stark

    (MPI for Biophysical Chemistry)

Abstract

The U2 small nuclear ribonucleoprotein (snRNP) has an essential role in the selection of the precursor mRNA branch-site adenosine, the nucleophile for the first step of splicing1. Stable addition of U2 during early spliceosome formation requires the DEAD-box ATPase PRP52–7. Yeast U2 small nuclear RNA (snRNA) nucleotides that form base pairs with the branch site are initially sequestered in a branchpoint-interacting stem–loop (BSL)8, but whether the human U2 snRNA folds in a similar manner is unknown. The U2 SF3B1 protein, a common mutational target in haematopoietic cancers9, contains a HEAT domain (SF3B1HEAT) with an open conformation in isolated SF3b10, but a closed conformation in spliceosomes11, which is required for stable interaction between U2 and the branch site. Here we report a 3D cryo-electron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 Å and combine it with protein crosslinking data to determine the molecular architecture of this snRNP. Our structure reveals that SF3B1HEAT interacts with PRP5 and TAT-SF1, and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a BSL that is sandwiched between PRP5, TAT-SF1 and SF3B1HEAT. Thus, substantial remodelling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2–branch-site helix. Our studies provide a structural explanation of why TAT-SF1 must be displaced before the stable addition of U2 to the spliceosome, and identify RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.

Suggested Citation

  • Zhenwei Zhang & Cindy L. Will & Karl Bertram & Olexandr Dybkov & Klaus Hartmuth & Dmitry E. Agafonov & Romina Hofele & Henning Urlaub & Berthold Kastner & Reinhard Lührmann & Holger Stark, 2020. "Molecular architecture of the human 17S U2 snRNP," Nature, Nature, vol. 583(7815), pages 310-313, July.
  • Handle: RePEc:nat:nature:v:583:y:2020:i:7815:d:10.1038_s41586-020-2344-3
    DOI: 10.1038/s41586-020-2344-3
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    Cited by:

    1. Lei Shen & Xiaokuang Ma & Yuanyuan Wang & Zhihao Wang & Yi Zhang & Hoang Quoc Hai Pham & Xiaoqun Tao & Yuehua Cui & Jing Wei & Dimitri Lin & Tharindumala Abeywanada & Swanand Hardikar & Levon Halabeli, 2024. "Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Santiago Martínez-Lumbreras & Lena K. Träger & Miriam M. Mulorz & Marco Payr & Varvara Dikaya & Clara Hipp & Julian König & Michael Sattler, 2024. "Intramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Fenghua Yang & Tong Bian & Xiechao Zhan & Zhe Chen & Zhihan Xing & Nicolas A. Larsen & Xiaofeng Zhang & Yigong Shi, 2023. "Mechanisms of the RNA helicases DDX42 and DDX46 in human U2 snRNP assembly," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Zachary W. Dwyer & Jeffrey A. Pleiss, 2023. "The problem of selection bias in studies of pre-mRNA splicing," Nature Communications, Nature, vol. 14(1), pages 1-5, December.

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