Phosphorylation-mediated conformational change regulates human SLFN11

Kugler, Michael; Metzner, Felix J.; Witte, Gregor; Hopfner, Karl-Peter; Lammens, Katja (2024): Phosphorylation-mediated conformational change regulates human SLFN11. Nature Communications, 15: 10500. ISSN 2041-1723

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.

• Dokumententyp: Artikel (LMU)
• Organisationseinheit (Fakultäten): 18 Chemie und Pharmazie > Department Biochemie; 18 Chemie und Pharmazie > GenZentrum
• DFG-Fachsystematik der Wissenschaftsbereiche: Naturwissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892