Phosphorylation-mediated conformational change regulates human SLFN11

Michael Kugler, Felix J. Metzner, Gregor Witte, Karl-Peter Hopfner and Katja Lammens ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54833-7

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