2007 Fiscal Year Final Research Report Summary
Discovery of novel anti-cancer drug : Elucidation of the regulatory function of endogenous 4E-binding protein for eukaryotic initiation factor 4E
| Project/Area Number |
18590085
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
TOMOO Koji Osaka University of Pharmaceutical Sciences, Pharmacy, Associate Professor (70257898)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Initiation factor 4E / 4E-binding protein / Interaction / Surface plasmon resonance / MD simulation |
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| Research Abstract |
Eukaryotic initiation factor 4E (eIF4E) is a master switch that controls eukaryotic translation, because the binding of eIF4E to the cap structure is required for the initiation of the mRNA translation. The cap binding of eIF4E is controlled by endogenous 4E-binding protein (4EBP) through the binding to eIF4E. The crystal structure of the m^7GpppA-eIF4E-4E-BP1peptide ternary complex clarified the 4EBP binding pocket of eIF4E and the binding mode of 4EBP at the atomic level. However, the regulatory function of full-length 4EBP for eIF4E has not yet been satisfactorily elucidated at the atomic level, because the N- and C-terminal sequences remain unstructured or structurally flexible. In recent years, the functional and biological importance of the flexible sequence has received much attention. Under such situation, to elucidate the function of the flexible sequence of 4EBP, we investigated the function of the N- and C-terminal flexible sequences of 4EBP2 for the interaction with eIF4E by surface plasmon resonance (SPR) analysis using the sequentially N-terminal or C-terminal-residue-deleted 4EBP2 mutants. Consequently, it was clarified for the first time that the C-terminal flexible region of 4EBP2, but not the N-terminal one, plays an important role in the interaction with eIF4E as well as the central Y (X)4Lf sequence. This is the first report on the functional role of the 4EBP C-terminal flexible region and is important to understand the regulation mechanism of the eIF4E function by the 4EBP isoform.
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