Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 25, Issue 3, Pages 208-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0030-z
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Funding
- US National Institutes of Health (NIH) [GM51266, GM113078]
- Knut and Alice Wallenberg Foundation (RiboCORE)
- Swedish Research Council
- Human Frontier Science Program
- Kahn Family Foundation
- Ernest and Bonnie Beutler Research Program
- Flight Attendant Medical Research Institute (FAMRI)
- Israeli Centers of Excellence (I-CORE) Program (ISF) [41/11, 1796/12]
- Human Frontier Science Program long-term fellowship
- NSF Science and Technology Centers [NSF-1231306]
- Stanford Bio-X fellowship
- Knut and Alice Wallenberg Foundation postdoc fellowship
- US Department of Energy, Office of Biological and Environmental Research
- NIH, US National Center for Research Resources, Biomedical Technology Program
- US National Institute of General Medical Sciences
- Howard Hughes Medical Institute (HHMI)
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Chemical modifications of mRNA may regulate many aspects of mRNA processing and protein synthesis. Recently, 2 '-O-methylation of nucleotides was identified as a frequent modification in translated regions of human mRNA, showing enrichment in codons for certain amino acids. Here, using single-molecule, bulk kinetics and structural methods, we show that 2 '-O-methylation within coding regions of mRNA disrupts key steps in codon reading during cognate tRNA selection. Our results suggest that 2 '-O-methylation sterically perturbs interactions of ribosomal-monitoring bases (G530, A1492 and A1493) with cognate codon-anticodon helices, thereby inhibiting downstream GTP hydrolysis by elongation factor Tu (EF-Tu) and A-site tRNA accommodation, leading to excessive rejection of cognate aminoacylated tRNAs in initial selection and proofreading. Our current and prior findings highlight how chemical modifications of mRNA tune the dynamics of protein synthesis at different steps of translation elongation.
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