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Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA

Author

Listed:
  • Lorenzo Baronti

    (Karolinska Institute)

  • Ileana Guzzetti

    (Karolinska Institute)

  • Parisa Ebrahimi

    (University at Albany, State University of New York)

  • Sarah Friebe Sandoz

    (Karolinska Institute)

  • Emilie Steiner

    (Karolinska Institute
    Laboratoire SABNP, UMR INSERM 1204, Université d’Evry-Val-d’Essonne–Université Paris-Saclay)

  • Judith Schlagnitweit

    (Karolinska Institute)

  • Bastian Fromm

    (The Wenner-Gren Institute, Stockholm University)

  • Luis Silva

    (Karolinska Institute)

  • Carolina Fontana

    (Karolinska Institute
    Facultad de Química and CENUR Litoral Norte, Universidad de la República)

  • Alan A. Chen

    (University at Albany, State University of New York)

  • Katja Petzold

    (Karolinska Institute)

Abstract

MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the ‘seed’ region of the miRNA and its counterpart mRNA1. Here we use R1ρ relaxation-dispersion nuclear magnetic resonance2 and molecular simulations3 to reveal a dynamic switch—based on the rearrangement of a single base pair in the miRNA–mRNA duplex—that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago4,5. Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA–mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial ‘screening’ state to an ‘active’ state, and unveil the role of the RNA duplex beyond the seed in Ago2.

Suggested Citation

  • Lorenzo Baronti & Ileana Guzzetti & Parisa Ebrahimi & Sarah Friebe Sandoz & Emilie Steiner & Judith Schlagnitweit & Bastian Fromm & Luis Silva & Carolina Fontana & Alan A. Chen & Katja Petzold, 2020. "Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA," Nature, Nature, vol. 583(7814), pages 139-144, July.
    • Handle: RePEc:nat:nature:v:583:y:2020:i:7814:d:10.1038_s41586-020-2336-3
    DOI: 10.1038/s41586-020-2336-3
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    Cited by:

    1. Ge Han & Yi Xue, 2022. "Rational design of hairpin RNA excited states reveals multi-step transitions," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Ainan Geng & Laura Ganser & Rohit Roy & Honglue Shi & Supriya Pratihar & David A. Case & Hashim M. Al-Hashimi, 2023. "An RNA excited conformational state at atomic resolution," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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