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Kang, H.-S. ; Sanchez-Rico, C. ; Ebersberger, S.* ; Sutandy, F.X.R.* ; Busch, A.* ; Welte, T.* ; Stehle, R.* ; Hipp, C.* ; Schulz, L.* ; Buchbender, A.* ; Zarnack, K.* ; König, J.* ; Sattler, M.

An autoinhibitory intramolecular interaction proof-reads RNA recognition by the essential splicing factor U2AF2.

Proc. Natl. Acad. Sci. U.S.A. 117, 7140-7149 (2020)
Verlagsversion DOI PMC
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The recognition of cis-regulatory RNA motifs in human transcripts by RNA binding proteins (RBPs) is essential for gene regulation. The molecular features that determine RBP specificity are often poorly understood. Here, we combined NMR structural biology with high-throughput iCLIP approaches to identify a regulatory mechanism for U2AF2 RNA recognition. We found that the intrinsically disordered linker region connecting the two RNA recognition motif (RRM) domains of U2AF2 mediates autoinhibitory intramolecular interactions to reduce nonproductive binding to weak Py-tract RNAs. This proofreading favors binding of U2AF2 at stronger Py-tracts, as required to define 3' splice sites at early stages of spliceosome assembly. Mutations that impair the linker autoinhibition enhance the affinity for weak Py-tracts result in promiscuous binding of U2AF2 along mRNAs and impact on splicing fidelity. Our findings highlight an important role of intrinsically disordered linkers to modulate RNA interactions of multidomain RBPs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Splicing ; Protein-rna Interactions ; U2 Auxiliary Factor ; Structural Biology ; Iclip; Pre-messenger-rna; Protein Structures; Branchpoint Sequence; Site Recognition; Structural Basis; Nmr; Program; Equilibrium; Specificity; Alignment
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 117, Heft: 13, Seiten: 7140-7149 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
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 10.1073/pnas.1913483117
WOS ID WOS:000523188100032
Scopus ID 85082765639
PubMed ID 32188783
Erfassungsdatum 2020-04-01
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