eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3877-82. doi: 10.1073/pnas.1216862110. Epub 2013 Feb 19.


Recognition of the methyl-7-guanosine (m(7)G) cap structure on mRNA is an essential feature of mRNA metabolism and thus gene expression. Eukaryotic translation initiation factor 4E (eIF4E) promotes translation, mRNA export, proliferation, and oncogenic transformation dependent on this cap-binding activity. eIF4E-cap recognition is mediated via complementary charge interactions of the positively charged m(7)G cap between the negative π-electron clouds from two aromatic residues. Here, we demonstrate that a variant subfamily, eIF4E3, specifically binds the m(7)G cap in the absence of an aromatic sandwich, using instead a different spatial arrangement of residues to provide the necessary electrostatic and van der Waals contacts. Contacts are much more extensive between eIF4E3-cap than other family members. Structural analyses of other cap-binding proteins indicate this recognition mode is atypical. We demonstrate that eIF4E3 relies on this cap-binding activity to act as a tumor suppressor, competing with the growth-promoting functions of eIF4E. In fact, reduced eIF4E3 in high eIF4E cancers suggests that eIF4E3 underlies a clinically relevant inhibitory mechanism that is lost in some malignancies. Taken together, there is more structural plasticity in cap recognition than previously thought, and this is physiologically relevant.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biophysical Phenomena
  • Cell Transformation, Neoplastic
  • Conserved Sequence
  • Eukaryotic Initiation Factor-4E / chemistry
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Guanosine / analogs & derivatives*
  • Guanosine / chemistry
  • Guanosine / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • RNA Caps / chemistry
  • RNA Caps / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Static Electricity
  • Thermodynamics
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • 8-methylguanosine
  • Eukaryotic Initiation Factor-4E
  • RNA Caps
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • eIF4E3 protein, human
  • Guanosine

Associated data

  • PDB/4B6U
  • PDB/4B6V