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TitlePhosphorylation-mediated conformational change regulates human SLFN11.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10500, Year 2024
Publish dateDec 3, 2024
AuthorsMichael Kugler / Felix J Metzner / Gregor Witte / Karl-Peter Hopfner / Katja Lammens /
PubMed AbstractHuman 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 linksNat Commun / PubMed:39627193 / PubMed Central
MethodsEM (single particle)
Resolution2.64 - 3.72 Å
Structure data

EMDB-19912, PDB-9erd:
Human SLFN11 S753D monomer
Method: EM (single particle) / Resolution: 3.72 Å

EMDB-19913, PDB-9ere:
SLFN11 dimer bound to tRNA-Leu-TAA
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-19914, PDB-9erf:
SLFN11 dimer bound to tRNA-Met-CAT
Method: EM (single particle) / Resolution: 2.64 Å

EMDB-51456, PDB-9gmw:
SLFN11 WT dimer bound to tRNA-Leu-TAA (pre-cleavage state)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-51457, PDB-9gmx:
SLFN11 WT dimer bound to tRNA-Leu-TAA (post-cleavage state)
Method: EM (single particle) / Resolution: 2.82 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-ZN:
Unknown entry

ChemComp-MN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE / phosphomimetic / ATP binding / monomeric / tRNA / endoribonuclease activity / dimeric

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