A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation

Junyan Lu, Chenxiao Jiang, Xiaojing Li, Lizhi Jiang, Zengxia Li, Tilman Schneider-Poetsch, Jianwei Liu, Kunqian Yu, Jun Liu, Hualiang Jiang, Cheng Luo, Yongjun Dang

Research output: Contribution to journalArticle

Abstract

Eukaryotic translation initiation factor eIF4AI, the founding member of DEAD-box helicases, undergoes ATP hydrolysis-coupled conformational changes to unwind mRNA secondary structures during translation initiation. However, the mechanism of its coupled enzymatic activities remains unclear. Here we report that a gating mechanism for Pi release controlled by the inter-domain linker of eIF4AI regulates the coupling between ATP hydrolysis and RNA unwinding. Molecular dynamic simulations and experimental results revealed that, through forming a hydrophobic core with the conserved SAT motif of the N-terminal domain and I357 from the C-terminal domain, the linker gated the release of Pi from the hydrolysis site, which avoided futile hydrolysis cycles of eIF4AI. Further mutagenesis studies suggested this linker also plays an auto-inhibitory role in the enzymatic activity of eIF4AI, which may be essential for its function during translation initiation. Overall, our results reveal a novel regulatory mechanism that controls eIF4AI-mediated mRNA unwinding and can guide further mechanistic studies on other DEADbox helicases.

Original languageEnglish (US)
Pages (from-to)10157-10167
Number of pages11
JournalNucleic Acids Research
Volume43
Issue number21
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Genetics

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    Lu, J., Jiang, C., Li, X., Jiang, L., Li, Z., Schneider-Poetsch, T., Liu, J., Yu, K., Liu, J., Jiang, H., Luo, C., & Dang, Y. (2015). A gating mechanism for Pi release governs the mRNA unwinding by eIF4AI during translation initiation. Nucleic Acids Research, 43(21), 10157-10167. https://doi.org/10.1093/nar/gkv1033