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Molecular basis for the calcium-dependent activation of the ribonuclease EndoU

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  • Florian Malard

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212
    Univ. Bordeaux, CNRS, INSERM, IECB, US1, UAR 3033)

  • Kristen Dias

    (University of California at Riverside)

  • Margaux Baudy

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212
    Univ. Bordeaux, CNRS, INSERM, IECB, US1, UAR 3033)

  • Stéphane Thore

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212)

  • Brune Vialet

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212)

  • Philippe Barthélémy

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212)

  • Sébastien Fribourg

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212)

  • Fedor V. Karginov

    (University of California at Riverside)

  • Sébastien Campagne

    (Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212
    Univ. Bordeaux, CNRS, INSERM, IECB, US1, UAR 3033)

Abstract

Ribonucleases (RNases) are ubiquitous enzymes that process or degrade RNA, essential for cellular functions and immune responses. The EndoU-like superfamily includes endoribonucleases conserved across bacteria, eukaryotes, and certain viruses, with an ancient evolutionary link to the ribonuclease A-like superfamily. Both bacterial EndoU and animal RNase A share a similar fold and function independently of cofactors. In contrast, the eukaryotic EndoU catalytic domain requires divalent metal ions for catalysis, possibly due to an N-terminal extension near the catalytic core. In this study, we use biophysical and computational techniques along with in vitro assays to investigate the calcium-dependent activation of human EndoU. We determine the crystal structure of EndoU bound to calcium and find that calcium binding remote from the catalytic triad triggers water-mediated intramolecular signaling and structural changes, activating the enzyme through allostery. Calcium binding involves residues from both the catalytic core and the N-terminal extension, indicating that the N-terminal extension interacts with the catalytic core to modulate activity in response to calcium. Our findings suggest that similar mechanisms may be present across all eukaryotic EndoUs, highlighting a unique evolutionary adaptation that connects endoribonuclease activity to cellular signaling in eukaryotes.

Suggested Citation

  • Florian Malard & Kristen Dias & Margaux Baudy & Stéphane Thore & Brune Vialet & Philippe Barthélémy & Sébastien Fribourg & Fedor V. Karginov & Sébastien Campagne, 2025. "Molecular basis for the calcium-dependent activation of the ribonuclease EndoU," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58462-6
    DOI: 10.1038/s41467-025-58462-6
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