The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity.

Binding Sites HeLa Cells Humans Models, Molecular Nucleotide Motifs Protein Binding Protein Interaction Domains and Motifs RNA / chemistry RNA Recognition Motif RNA Splicing RNA Stability RNA-Binding Protein FUS / chemistry Structure-Activity Relationship Zinc Fingers
Arg-Gly-Gly RNA recognition motif alternative-splicing amyotrophic lateral sclerosis frontotemporal lobar degeneration fused in sarcoma nuclear magnetic resonance spectroscopy protein-RNA complex ribonucleoprotein zinc finger

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
07 02 2019
Historique:
received: 07 05 2018
revised: 21 09 2018
accepted: 13 11 2018
pubmed: 26 12 2018
medline: 31 5 2019
entrez: 25 12 2018
Statut: ppublish

Résumé

Fused in sarcoma (FUS) is an RNA binding protein involved in regulating many aspects of RNA processing and linked to several neurodegenerative diseases. Transcriptomics studies indicate that FUS binds a large variety of RNA motifs, suggesting that FUS RNA binding might be quite complex. Here, we present solution structures of FUS zinc finger (ZnF) and RNA recognition motif (RRM) domains bound to RNA. These structures show a bipartite binding mode of FUS comprising of sequence-specific recognition of a NGGU motif via the ZnF and an unusual shape recognition of a stem-loop RNA via the RRM. In addition, sequence-independent interactions via the RGG repeats significantly increase binding affinity and promote destabilization of structured RNA conformation, enabling additional binding. We further show that disruption of the RRM and ZnF domains abolishes FUS function in splicing. Altogether, our results rationalize why deciphering the RNA binding mode of FUS has been so challenging.

Identifiants

DOI: 10.1016/j.molcel.2018.11.012 PMID: 30581145
pubmed: 30581145
pii: S1097-2765(18)30982-1
doi: 10.1016/j.molcel.2018.11.012
pii:
doi:

Substances chimiques

FUS protein, human 0
RNA-Binding Protein FUS 0
RNA 63231-63-0

Types de publication

Comparative Study Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

490-504.e6

Informations de copyright

Copyright © 2018 Elsevier Inc. All rights reserved.

Auteurs

Fionna E Loughlin (FE)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland; Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800 VIC, Australia. Electronic address: fionna.loughlin@monash.edu.

Peter J Lukavsky (PJ)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.

Tamara Kazeeva (T)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.

Stefan Reber (S)

Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.

Eva-Maria Hock (EM)

Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.

Martino Colombo (M)

Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.

Christine Von Schroetter (C)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.

Phillip Pauli (P)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.

Antoine Cléry (A)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.

Oliver Mühlemann (O)

Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.

Magdalini Polymenidou (M)

Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.

Marc-David Ruepp (MD)

Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.

Frédéric H-T Allain (FH)

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland. Electronic address: allain@mol.biol.ethz.ch.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › Motifs nucléotidiques › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Motifs et domaines d'intéraction protéique › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Motifs de liaison à l'ARN › Motif de reconnaissance de l'ARN › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Stabilité de l'ARN › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Protéines à motif de reconnaissance de l'ARN › Ribonucléoprotéines nucléaires hétérogènes › Protéine FUS de liaison à l'ARN › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › The Solution Structure of FUS Bound to RNA...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Doigts de zinc › The Solution Structure of FUS Bound to RNA...