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2'-O-methylation in mRNA disrupts tRNA decoding during translation elongation

Choi, Junhong (author)
Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.;Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.
Indrisiunaite, Gabriele (author)
Uppsala universitet,Molekylärbiologi
DeMirci, Hasan (author)
SLAC Natl Accelerator Lab, Stanford PULSE Inst, Menlo Pk, CA USA.;SLAC Natl Accelerator Lab, Biosci Div, Menlo Pk, CA USA.
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Leong, Ka-Weng (author)
Uppsala universitet,Molekylärbiologi
Wang, Jinfan (author)
Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.
Petrov, Alexey (author)
Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.;Auburn Univ, Dept Biol Sci, Auburn, AL 36849 USA.
Prabhakarl, Arjun (author)
Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.;Stanford Univ, Program Biophys, Stanford, CA 94305 USA.
Rechavi, Gideon (author)
Chaim Sheba Med Ctr, Canc Res Ctr, Tel Hashomer, Israel.;Chaim Sheba Med Ctr, Wohl Ctr Translat Med, Tel Hashomer, Israel.;Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel.
Dominissini, Dan (author)
Chaim Sheba Med Ctr, Canc Res Ctr, Tel Hashomer, Israel.;Chaim Sheba Med Ctr, Wohl Ctr Translat Med, Tel Hashomer, Israel.;Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel.
He, Chuan (author)
Univ Chicago, Dept Biochem & Mol Biol, Dept Chem, 920 E 58Th St, Chicago, IL 60637 USA.;Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA.;Univ Chicago, Howard Hughes Med Inst, 5841 S Maryland Ave, Chicago, IL 60637 USA.
Ehrenberg, Måns (author)
Uppsala universitet,Molekylärbiologi
Puglisi, Joseph D. (author)
Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.
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Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA;Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA. Molekylärbiologi (creator_code:org_t)
2018-02-19
2018
English.
In: Nature Structural & Molecular Biology. - : Springer Nature. - 1545-9993 .- 1545-9985. ; 25:3, s. 208-216
  • Journal article (peer-reviewed)
Abstract Subject headings
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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.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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