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

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

doi:10.1016/j.molcel.2018.11.012

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

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

Basic and Clinical Neuroscience

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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.

Original language	English
Pages (from-to)	490-504.e6
Journal	MOLECULAR CELL
Volume	73
Issue number	3
Early online date	20 Dec 2018
DOIs	https://doi.org/10.1016/j.molcel.2018.11.012
Publication status	Published - 7 Feb 2019

Keywords

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

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10.1016/j.molcel.2018.11.012

The Solution Structure of_LOUGHLIN_Accepted13November2018_GREEN AAMAccepted author manuscript, 14.6 MB

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Loughlin, F. E., Lukavsky, P. J., Kazeeva, T., Reber, S., Hock, E.-M., Colombo, M., Von Schroetter, C., Pauli, P., Cléry, A., Mühlemann, O., Polymenidou, M., Ruepp, M.-D., & Allain, F. H.-T. (2019). The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity. MOLECULAR CELL, 73(3), 490-504.e6. https://doi.org/10.1016/j.molcel.2018.11.012

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

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.",

keywords = "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",

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Loughlin, FE, Lukavsky, PJ, Kazeeva, T, Reber, S, Hock, E-M, Colombo, M, Von Schroetter, C, Pauli, P, Cléry, A, Mühlemann, O, Polymenidou, M, Ruepp, M-D & Allain, FH-T 2019, 'The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity', MOLECULAR CELL, vol. 73, no. 3, pp. 490-504.e6. https://doi.org/10.1016/j.molcel.2018.11.012

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T1 - The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity

AU - Loughlin, Fionna E.

AU - Lukavsky, Peter J.

AU - Kazeeva, Tamara

AU - Reber, Stefan

AU - Hock, Eva-Maria

AU - Colombo, Martino

AU - Von Schroetter, Christine

AU - Pauli, Philip

AU - Cléry, Antoine

AU - Mühlemann, Oliver

AU - Polymenidou, Magdalini

AU - Ruepp, Marc-David

AU - Allain, Frédéric H.-T.

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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.

KW - Arg-Gly-Gly

KW - RNA recognition motif

KW - alternative-splicing

KW - amyotrophic lateral sclerosis

KW - frontotemporal lobar degeneration

KW - fused in sarcoma

KW - nuclear magnetic resonance spectroscopy

KW - protein-RNA complex

KW - ribonucleoprotein

KW - zinc finger

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U2 - 10.1016/j.molcel.2018.11.012

DO - 10.1016/j.molcel.2018.11.012

M3 - Article

SN - 1097-2765

VL - 73

SP - 490-504.e6

JO - MOLECULAR CELL

JF - MOLECULAR CELL

IS - 3

ER -

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

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Keywords

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