Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA.

Nature
Lorenzo BarontiKatja Petzold

Abstract

MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the 'seed' region of the miRNA and its counterpart mRNA1. Here we use R1ρ relaxation-dispersion nuclear magnetic resonance2 and molecular simulations3 to reveal a dynamic switch-based on the rearrangement of a single base pair in the miRNA-mRNA duplex-that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago4,5. Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA-mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial 'screening' state to an 'active' state, and unveil the role of the RNA duplex beyond the seed in Ago2.

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Citations

May 31, 2020·Nature Structural & Molecular Biology·François Major
Jan 1, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Marcello CeciNicla Romano
Dec 23, 2020·Chembiochem : a European Journal of Chemical Biology·Abdallah S AbdelsattarFareed Aboul-Ela
Nov 6, 2020·Scientific Reports·A Ben ImeddoureneO Mauffret
Apr 10, 2021·Current Opinion in Structural Biology·Bei LiuHashim M Al-Hashimi
Jun 18, 2021·Current Protocols·Hampus KarlssonKatja Petzold
Jul 3, 2021·Cells·Danyel Fernandes ContilianiTiago Campos Pereira

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Methods Mentioned

BETA
X-ray
NMR
nuclear magnetic resonance
electrophoretic mobility shift assay
gel-filtration
gel filtration
transfection

Software Mentioned

RNA FRABASE
Fold
GROMACS
TargetScan
Sym
REMD
ImageJ
MC
EMSA

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