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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS	eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation Tobias Schmidt , Adrianna Dabrowska , Joseph A. Waldron , Kelly Hodge , Grigorios Koulouras , Mads Gabrielsen , June Munro , David C. Tack , Gemma Harris , Ewan Mcghee , David Scott , Leo m. Carlin , Danny Huang , John Le quesne , Sara Zanivan , Ania Wilczynska , Martin Bushell Nucleic Acids Research 168 DOI: 10.1093/nar/gkad030 Diamond Proposal Number(s): [21657] Open Access Show Abstract ▼ 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.	Feb 2023

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B21-High Throughput SAXS

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