Structural scaffold for eIF4E binding selectivity of 4E-BP isoforms: crystal structure of eIF4E binding region of 4E-BP2 and its comparison with that of 4E-BP1

J Pept Sci. 2011 Sep;17(9):650-7. doi: 10.1002/psc.1384. Epub 2011 Jun 10.

Abstract

To clarify the higher eukaryotic initiation factor 4E (eIF4E) binding selectivity of 4E-binding protein 2 (4E-BP2) than of 4E-BP1, as determined by Trp fluorescence analysis, the crystal structure of the eIF4E binding region of 4E-BP2 in complex with m(7) GTP-bound human eIF4E has been determined by X-ray diffraction analysis and compared with that of 4E-BP1. The crystal structure revealed that the Pro47-Ser65 moiety of 4E-BP2 adopts a L-shaped conformation involving extended and α-helical structures and extends over the N-terminal loop and two different helix regions of eIF4E through hydrogen bonds, and electrostatic and hydrophobic interactions; these features were similarly observed for 4E-BP1. Although the pattern of the overall interaction of 4E-BP2 with eIF4E was similar to that of 4E-BP1, a notable difference was observed for the 60-63 sequence in relation to the conformation and binding selectivity of the 4E-BP isoform, i.e. Met-Glu-Cys-Arg for 4E-BP1 and Leu-Asp-Arg-Arg for 4E-BP2. In this paper, we report that the structural scaffold of the eIF4E binding preference for 4E-BP2 over 4E-BP1 is based on the stacking of the Arg63 planar side chain on the Trp73 indole ring of eIF4E and the construction of a compact hydrophobic space around the Trp73 indole ring by the Leu59-Leu60 sequence of 4E-BP2.

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle Proteins
  • Crystallography, X-Ray
  • Eukaryotic Initiation Factor-4E / chemistry*
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factors / chemistry*
  • Eukaryotic Initiation Factors / metabolism
  • Humans
  • Hydrogen Bonding
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry
  • Phosphoproteins / chemistry*
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Isoforms / chemistry*
  • Protein Isoforms / metabolism
  • Protein Structure, Secondary*
  • Sequence Alignment

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • EIF4EBP2 protein, human
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Multiprotein Complexes
  • Phosphoproteins
  • Protein Isoforms