Aromatic side-chain conformational switch on the surface of the RNA Recognition Motif enables RNA discrimination

Nana Diarra dit Konté, Miroslav Krepl, Fred F. Damberger, Nina Ripin, Olivier Duss, Jiří Šponer and Frédéric H.-T. Allain ()
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Nana Diarra dit Konté: Institute of Molecular Biology and Biophysics
Miroslav Krepl: Academy of Sciences of the Czech Republic
Fred F. Damberger: Institute of Molecular Biology and Biophysics
Nina Ripin: Institute of Molecular Biology and Biophysics
Olivier Duss: Institute of Molecular Biology and Biophysics
Jiří Šponer: Academy of Sciences of the Czech Republic
Frédéric H.-T. Allain: Institute of Molecular Biology and Biophysics

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract The cyclooxygenase-2 is a pro-inflammatory and cancer marker, whose mRNA stability and translation is regulated by the CUG-binding protein 2 interacting with AU-rich sequences in the 3′ untranslated region. Here, we present the solution NMR structure of CUG-binding protein 2 RRM3 in complex with 5′-UUUAA-3′ originating from the COX-2 3′-UTR. We show that RRM3 uses the same binding surface and protein moieties to interact with AU- and UG-rich RNA motifs, binding with low and high affinity, respectively. Using NMR spectroscopy, isothermal titration calorimetry and molecular dynamics simulations, we demonstrate that distinct sub-states characterized by different aromatic side-chain conformations at the RNA-binding surface allow for high- or low-affinity binding with functional implications. This study highlights a mechanism for RNA discrimination possibly common to multiple RRMs as several prominent members display a similar rearrangement of aromatic residues upon binding their targets.

Date: 2017
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DOI: 10.1038/s41467-017-00631-3

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