Labeled EF-Tus for rapid kinetic studies of pretranslocation complex formation

ACS Chem Biol. 2014 Oct 17;9(10):2421-31. doi: 10.1021/cb500409y. Epub 2014 Aug 22.

Abstract

The universally conserved translation elongation factor EF-Tu delivers aminoacyl(aa)-tRNA in the form of an aa-tRNA·EF-Tu·GTP ternary complex (TC) to the ribosome where it binds to the cognate mRNA codon within the ribosomal A-site, leading to formation of a pretranslocation (PRE) complex. Here we describe preparation of QSY9 and Cy5 derivatives of the variant E348C-EF-Tu that are functional in translation elongation. Together with fluorophore derivatives of aa-tRNA and of ribosomal protein L11, located within the GTPase associated center (GAC), these labeled EF-Tus allow development of two new FRET assays that permit the dynamics of distance changes between EF-Tu and both L11 (Tu-L11 assay) and aa-tRNA (Tu-tRNA assay) to be determined during the decoding process. We use these assays to examine: (i) the relative rates of EF-Tu movement away from the GAC and from aa-tRNA during decoding, (ii) the effects of the misreading-inducing antibiotics streptomycin and paromomycin on tRNA selection at the A-site, and (iii) how strengthening the binding of aa-tRNA to EF-Tu affects the rate of EF-Tu movement away from L11 on the ribosome. These FRET assays have the potential to be adapted for high throughput screening of ribosomal antibiotics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Guanosine Triphosphate / metabolism
  • Kinetics
  • Models, Molecular
  • Mutation / genetics
  • Peptide Elongation Factor Tu / chemistry
  • Peptide Elongation Factor Tu / genetics
  • Peptide Elongation Factor Tu / metabolism*
  • Protein Biosynthesis / physiology*
  • Protein Conformation
  • RNA, Transfer, Amino Acyl / chemistry*
  • RNA, Transfer, Amino Acyl / metabolism
  • Ribosomal Proteins / metabolism*
  • Ribosomes / physiology*

Substances

  • Escherichia coli Proteins
  • RNA, Transfer, Amino Acyl
  • Ribosomal Proteins
  • ribosomal protein L11
  • Guanosine Triphosphate
  • Peptide Elongation Factor Tu