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| Title | Phosphorylation-mediated conformational change regulates human SLFN11. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 10500, Year 2024 |
| Publish date | Dec 3, 2024 |
Authors | Michael Kugler / Felix J Metzner / Gregor Witte / Karl-Peter Hopfner / Katja Lammens / ![]() |
| PubMed 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, ...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. |
External links | Nat Commun / PubMed:39627193 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.64 - 3.72 Å |
| Structure data | EMDB-19912, PDB-9erd: EMDB-19913, PDB-9ere: EMDB-19914, PDB-9erf: EMDB-51456, PDB-9gmw: EMDB-51457, PDB-9gmx: |
| Chemicals | ![]() ChemComp-MG: ![]() ChemComp-ATP: ![]() ChemComp-ZN: ![]() ChemComp-MN: |
| Source |
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Keywords | HYDROLASE / phosphomimetic / ATP binding / monomeric / tRNA / endoribonuclease activity / dimeric |
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homo sapiens (human)
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