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TitleMechanistic understanding of human SLFN11.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 5464, Year 2022
Publish dateSep 17, 2022
AuthorsFelix J Metzner / Simon J Wenzl / Michael Kugler / Stefan Krebs / Karl-Peter Hopfner / Katja Lammens /
PubMed AbstractSchlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to ...Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.
External linksNat Commun / PubMed:36115853 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 4.0 Å
Structure data

14690

7zel

EMDB-14690, PDB-7zel:
Human SLFN11 dimer apoenzyme
Method: EM (single particle) / Resolution: 2.8 Å

14691

7zep

EMDB-14691, PDB-7zep:
Human SLFN11 E209A dimer
Method: EM (single particle) / Resolution: 3.2 Å

14692

7zes

EMDB-14692, PDB-7zes:
Human SLFN11 dimer bound to ssDNA
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-14693: SLFN11 E209A monomer
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-14695: SLFN11 dimer bound to tRNA
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsHYDROLASE / tRNA endonuclease / single-strand DNA binding protein

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