Structural highlights
Function
IF4E_HUMAN Its translation stimulation activity is repressed by binding to the complex CYFIP1-FMR1 (By similarity). Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap.[1]
Publication Abstract from PubMed
Identifying new binding sites and poses that modify biological function are an important step towards drug discovery. We have identified a novel disulphide constrained peptide that interacts with the cap-binding site of eIF4E, an attractive therapeutic target that is commonly overexpressed in many cancers and plays a significant role in initiating a cancer specific protein synthesis program though binding the 5'cap (7'methyl-guanoisine) moiety found on mammalian mRNAs. The use of disulphide constrained peptides to explore intracellular biological targets is limited by their lack of cell permeability and the instability of the disulphide bond in the reducing environment of the cell, loss of which results in abrogation of binding. To overcome these challenges, the cap-binding site interaction motif was placed in a hypervariable loop on an VH domain, and then selections performed to select a molecule that could recapitulate the interaction of the peptide with the target of interest in a process termed Peptide Epitope Linker Evolution (PELE). A novel VH domain was identified that interacted with the eIF4E cap binding site with a nanomolar affinity and that could be intracellularly expressed in mammalian cells. Additionally, it was demonstrated to specifically modulate eIF4E function by decreasing cap-dependent translation and cyclin D1 expression, common effects of eIF4F complex disruption.
Development of a novel peptide aptamer that interacts with the eIF4E capped-mRNA binding site using peptide epitope linker evolution (PELE).,Frosi Y, Ng S, Lin YC, Jiang S, Ramlan SR, Lama D, Verma CS, Asial I, Brown CJ RSC Chem Biol. 2022 May 19;3(7):916-930. doi: 10.1039/d2cb00099g. eCollection, 2022 Jul 6. PMID:35866173[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tomoo K, Matsushita Y, Fujisaki H, Abiko F, Shen X, Taniguchi T, Miyagawa H, Kitamura K, Miura K, Ishida T. Structural basis for mRNA Cap-Binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural, and molecular dynamics simulation methods. Biochim Biophys Acta. 2005 Dec 1;1753(2):191-208. Epub 2005 Aug 24. PMID:16271312 doi:10.1016/j.bbapap.2005.07.023
- ↑ Frosi Y, Ng S, Lin YC, Jiang S, Ramlan SR, Lama D, Verma CS, Asial I, Brown CJ. Development of a novel peptide aptamer that interacts with the eIF4E capped-mRNA binding site using peptide epitope linker evolution (PELE). RSC Chem Biol. 2022 May 19;3(7):916-930. doi: 10.1039/d2cb00099g. eCollection, 2022 Jul 6. PMID:35866173 doi:http://dx.doi.org/10.1039/d2cb00099g
