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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Loughlin Fionna E., Lukavsky Peter J., Kazeeva Tamara, Reber Stefan, Hock Eva-Maria, Colombo Martino, Von Schroetter Christine, Pauli Phillip, Cléry Antoine, Mühlemann Oliver, Polymenidou Magdalini, Ruepp Marc-David, Allain Frédéric H.-T.,
Project Elucidating the biological function of FUS and its role in neurodegeneration
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Original article (peer-reviewed)

Journal Molecular Cell
Volume (Issue) 73
Page(s) 1-15
Title of proceedings Molecular Cell
DOI 10.1016/j.molcel.2018.11.012

Abstract

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,wepresent solution structures ofFUSzincfinger (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.
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