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Phosphorylation-mediated conformational change regulates human SLFN11

Author

Listed:
  • Michael Kugler

    (Ludwig-Maximilians-Universität München)

  • Felix J. Metzner

    (Ludwig-Maximilians-Universität München)

  • Gregor Witte

    (Ludwig-Maximilians-Universität München)

  • Karl-Peter Hopfner

    (Ludwig-Maximilians-Universität München)

  • Katja Lammens

    (Ludwig-Maximilians-Universität München)

Abstract

Human Schlafen 11 (SLFN11) is sensitizing cells to DNA damaging agents by irreversibly blocking stalled replication forks, making it a potential predictive biomarker in chemotherapy. Furthermore, SLFN11 acts as a pattern recognition receptor for single-stranded DNA (ssDNA) and functions as an antiviral restriction factor, targeting translation in a codon-usage-dependent manner through its endoribonuclease activity. However, the regulation of the various SLFN11 functions and enzymatic activities remains enigmatic. Here, we present cryo-electron microscopy (cryo-EM) structures of SLFN11 bound to tRNA-Leu and tRNA-Met that give insights into tRNA binding and cleavage, as well as its regulation by phosphorylation at S219 and T230. SLFN11 phosphomimetic mutant S753D adopts a monomeric conformation, shows ATP binding, but loses its ability to bind ssDNA and shows reduced ribonuclease activity. Thus, the phosphorylation site S753 serves as a conformational switch, regulating SLFN11 dimerization, as well as ATP and ssDNA binding, while S219 and T230 regulate tRNA recognition and nuclease activity.

Suggested Citation

  • Michael Kugler & Felix J. Metzner & Gregor Witte & Karl-Peter Hopfner & Katja Lammens, 2024. "Phosphorylation-mediated conformational change regulates human SLFN11," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54833-7
    DOI: 10.1038/s41467-024-54833-7
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    References listed on IDEAS

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    1. Justin Riper & Arleth O. Martinez-Claros & Lie Wang & Hannah E. Schneiderman & Sweta Maheshwari & Monica C. Pillon, 2025. "CryoEM structure of the SLFN14 endoribonuclease reveals insight into RNA binding and cleavage," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

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