DSSR-PyMOL cartoon-block schematics: PDB entry 6g99

PDB-id

6g99; DSSR-derived features in text and JSON formats

Class

RNA binding protein

Method

NMR

Summary

Solution structure of fus-znf bound to uggug

Reference

Loughlin FE, Lukavsky PJ, Kazeeva T, Reber S, Hock EM, Colombo M, Von Schroetter C, Pauli P, Clery A, Muhlemann O, Polymenidou M, Ruepp MD, Allain FH (2019): "The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity." Mol. Cell, 73, 490-504.e6. 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, 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.