Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 21, Pages 10157-10167Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv1033
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Funding
- Ministry of Science and Technology of China [2015CB910304]
- Hi-Tech Research and Development Program of China [2012AA020301, 2012AA01A305, 2012AA020302]
- National Natural Science Foundation of China [81430084, 21472208, 31270830, 21572038]
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Fudan University
- State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science [TMC201505]
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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 DEAD-box helicases.
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