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

Florian Malard, Kristen Dias, Margaux Baudy, Stéphane Thore, Brune Vialet, Philippe Barthélémy, Sébastien Fribourg (), Fedor V. Karginov () and Sébastien Campagne ()
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Florian Malard: Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212
Kristen Dias: University of California at Riverside
Margaux Baudy: Univ. Bordeaux, CNRS, INSERM, ARNA, UMR 5320, U1212
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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58462-6

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