Mechanistic understanding of human SLFN11.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 09 2022
17 09 2022
Historique:
received:
01
04
2022
accepted:
01
09
2022
entrez:
17
9
2022
pubmed:
18
9
2022
medline:
21
9
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36115853
doi: 10.1038/s41467-022-33123-0
pii: 10.1038/s41467-022-33123-0
pmc: PMC9482658
doi:
Substances chimiques
Antineoplastic Agents
0
Antiviral Agents
0
Apoenzymes
0
Nuclear Proteins
0
SLFN11 protein, human
0
Adenosine Triphosphate
8L70Q75FXE
DNA
9007-49-2
Interferons
9008-11-1
RNA, Transfer
9014-25-9
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5464Informations de copyright
© 2022. The Author(s).
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