Molecular Architecture of 4E-BP Translational Inhibitors Bound to eIF4E
| Autor: | Linda Ebertsch, Elisa Izaurralde, Lara Wohlbold, Cátia Igreja, Catrin Weiler, Ramona Weber, Oliver Weichenrieder, Daniel Peter |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Protein Conformation Amino Acid Motifs Cell Cycle Proteins Computational biology Biology Crystallography X-Ray Binding Competitive chemistry.chemical_compound Protein structure Peptide Initiation Factors Animals Drosophila Proteins Humans Phosphorylation Binding site Molecular Biology Adaptor Proteins Signal Transducing Binding Sites EIF4G Molecular Mimicry EIF4E Intracellular Signaling Peptides and Proteins Rational design Signal transducing adaptor protein Translation (biology) Cell Biology Phosphoproteins Recombinant Proteins Eukaryotic Initiation Factor-4E chemistry Biochemistry Carrier Proteins Eukaryotic Initiation Factor-4G |
| Zdroj: | Molecular Cell. 57:1074-1087 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2015.01.017 |
| Popis: | The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical and non-canonical eIF4E-binding motifs connected by a linker. The lack of high-resolution structures including the linkers, which contain phosphorylation sites, limits our understanding of how phosphorylation inhibits complex formation. Furthermore, the binding mechanism of the non-canonical motifs is poorly understood. Here, we present structures of human eIF4E bound to 4E-BP1 and fly eIF4E bound to Thor, 4E-T, and eIF4G. These structures reveal architectural elements that are unique to 4E-BPs and provide insight into the consequences of phosphorylation. Guided by these structures, we designed and crystallized a 4E-BP mimic that shows increased repressive activity. Our studies pave the way for the rational design of 4E-BP mimics as therapeutic tools to decrease translation during oncogenic transformation. |
| Databáze: | OpenAIRE |
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