eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation

DOI: 10.1093/nar/gkad030

Authors: Tobias Schmidt (Cancer Research UK Beatson Institute) , Adrianna Dabrowska (Cancer Research UK Beatson Institute; University of Glasgow; University of California, San Francisco) , Joseph A. Waldron (Cancer Research UK Beatson Institute) , Kelly Hodge (Cancer Research UK Beatson Institute) , Grigorios Koulouras (Cancer Research UK Beatson Institute) , Mads Gabrielsen (University of Glasgow) , June Munro (Cancer Research UK Beatson Institute) , David C. Tack (Spectrum Health Office of Research and Education) , Gemma Harris (Research Complex at Harwell) , Ewan Mcghee (Cancer Research UK Beatson Institute) , David Scott (Research Complex at Harwell; ISIS Spallation Neutron and Muon Source; University of Nottingham) , Leo m. Carlin (Cancer Research UK Beatson Institute; University of Glasgow) , Danny Huang (Cancer Research UK Beatson Institute; University of Glasgow) , John Le quesne (Cancer Research UK Beatson Institute; University of Glasgow) , Sara Zanivan (Cancer Research UK Beatson Institute; University of Glasgow) , Ania Wilczynska (Cancer Research UK Beatson Institute; University of Glasgow) , Martin Bushell (Cancer Research UK Beatson Institute; University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 168

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 21657

Abstract: Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5’UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5’UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS

Added On: 07/02/2023 15:38

Documents:
gkad030.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)