Publication details

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

Authors	LOUGHLIN F.E. LUKAVSKY Peter KAZEEVA T. REBER S. HOCK E.M. COLOMBO M. VON SCHROETTER C. PAULI P. CLERY A. MUHLEMANN O. POLYMENIDOU M. RUEPP M.D. ALLAIN F.H.T.
Year of publication	2019
Type	Article in Periodical
Magazine / Source	Molecular Cell
MU Faculty or unit	Central European Institute of Technology
Citation
web	https://www.sciencedirect.com/science/article/pii/S1097276518309821?via%3Dihub
Doi	http://dx.doi.org/10.1016/j.molcel.2018.11.012
Keywords	NUCLEAR IMPORT RECEPTOR; PHASE-SEPARATION; CRYSTAL-STRUCTURE; BINDING PROTEINS; NMR STRUCTURE; ZINC FINGERS; ALS; DOMAIN; GRANULES; IDENTIFICATION
Description	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.