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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

Research output: Contribution to journalArticle

Fionna E. Loughlin, Peter J. Lukavsky, Tamara Kazeeva, Stefan Reber, Eva-Maria Hock, Martino Colombo, Christine Von Schroetter, Philip Pauli, Antoine Cléry, Oliver Mühlemann, Magdalini Polymenidou, Marc-David Ruepp, Frédéric H.-T. Allain

Original languageEnglish
JournalMOLECULAR CELL
Early online date20 Dec 2018
DOIs
Publication statusPublished - 7 Feb 2019

King's Authors

Abstract

Fused in sarcoma (FUS) is an RNA binding protein involved in regulating many aspects of RNA process- ing and linked to several neurodegenerative dis- eases. 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-spe- cific 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 interac- tions via the RGG repeats significantly increase bind- ing 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. Alto- gether, our results rationalize why deciphering the RNA binding mode of FUS has been so challenging.

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