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

0485552 - BFÚ 2018 RIV GB eng J - Journal Article
Konte, N.D. - Krepl, Miroslav - Damberger, F.F. - Ripin, N. - Duss, O. - Šponer, Jiří - Allain, F.H.T.
Aromatic side-chain conformational switch on the surface of the RNA Recognition Motif enables RNA discrimination.
Nature Communications. Roč. 8, SEP2017 (2017), č. článku 654. E-ISSN 2041-1723
R&D Projects: GA ČR(CZ) GBP305/12/G034
Institutional support: RVO:68081707
Keywords : nmr structure determination * particle mesh ewald
OECD category: Biochemistry and molecular biology
Impact factor: 12.353, year: 2017

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.
Permanent Link: http://hdl.handle.net/11104/0280517