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Tants, J.-N. ; Fesser, S.* ; Kern, T. ; Stehle, R. ; Geerlof, A. ; Wunderlich, C.* ; Juen, M.* ; Hartlmüller, C. ; Böttcher, R.* ; Kunzelmann, S.* ; Lange, O.L.* ; Kreutz, C.* ; Förstemann, K.* ; Sattler, M.

Molecular basis for asymmetry sensing of siRNAs by the Drosophila Loqs-PD/Dcr-2 complex in RNA interference.

Nucleic Acids Res. 45, 12536-12550 (2017)
Verlagsversion Forschungsdaten DOI PMC
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RNA interference defends against RNA viruses and retro-elements within an organism's genome. It is triggered by duplex siRNAs, of which one strand is selected to confer sequence-specificity to the RNA induced silencing complex (RISC). In Drosophila, Dicer-2 (Dcr-2) and the double-stranded RNA binding domain (dsRBD) protein R2D2 form the RISC loading complex (RLC) and select one strand of exogenous siRNAs according to the relative thermodynamic stability of base-pairing at either end. Through genome editing we demonstrate that Loqs-PD, the Drosophila homolog of human TAR RNA binding protein (TRBP) and a paralog of R2D2, forms an alternative RLC with Dcr-2 that is required for strand choice of endogenous siRNAs in S2 cells. Two canonical dsRBDs in Loqs-PD bind to siRNAs with enhanced affinity compared to miRNA/miRNA* duplexes. Structural analysis, NMR and biophysical experiments indicate that the Loqs-PD dsRBDs can slide along the RNA duplex to the ends of the siRNA. A moderate but notable binding preference for the thermodynamically more stable siRNA end by Loqs-PD alone is greatly amplified in complex with Dcr-2 to initiate strand discrimination by asymmetry sensing in the RLC.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dsrna-binding Domain; Paramagnetic Relaxation Enhancement; Guide Strand Selection; Protein-kinase Pkr; Messenger-rnas; Self-renewal; Endo-sirnas; Stem-cells; Pathway; Risc
Sprache englisch
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Zeitschrift Nucleic Acids Research
Quellenangaben Band: 45, Heft: 21, Seiten: 12536-12550 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Oxford
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
DOI 10.1093/nar/gkx886
WOS ID WOS:000417691300041
Scopus ID 85039049476
PubMed ID 29040648
Erfassungsdatum 2017-10-25
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