title: 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.
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.
authors.affiliation: Laboratory of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Fukuyo
authors.forename: Yasuko
authors.initials: Y
authors.lastname: In
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishida
authors.forename: Koji
authors.initials: K
authors.lastname: Tomoo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C104151:EIF4EBP2 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D020033:Protein Isoforms