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Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation

The eIF4E-binding proteins (4E-BPs) are a diverse class of translation regulators that share a canonical eIF4E-binding motif (4E-BM) with eIF4G. Consequently, they compete with eIF4G for binding to eIF4E, thereby inhibiting translation initiation. Mextli (Mxt) is an unusual 4E-BP that promotes trans...

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Autores principales: Peter, Daniel, Weber, Ramona, Köne, Carolin, Chung, Min-Yi, Ebertsch, Linda, Truffault, Vincent, Weichenrieder, Oliver, Igreja, Cátia, Izaurralde, Elisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573856/
https://www.ncbi.nlm.nih.gov/pubmed/26294658
http://dx.doi.org/10.1101/gad.269068.115
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author Peter, Daniel
Weber, Ramona
Köne, Carolin
Chung, Min-Yi
Ebertsch, Linda
Truffault, Vincent
Weichenrieder, Oliver
Igreja, Cátia
Izaurralde, Elisa
author_facet Peter, Daniel
Weber, Ramona
Köne, Carolin
Chung, Min-Yi
Ebertsch, Linda
Truffault, Vincent
Weichenrieder, Oliver
Igreja, Cátia
Izaurralde, Elisa
author_sort Peter, Daniel
collection PubMed
description The eIF4E-binding proteins (4E-BPs) are a diverse class of translation regulators that share a canonical eIF4E-binding motif (4E-BM) with eIF4G. Consequently, they compete with eIF4G for binding to eIF4E, thereby inhibiting translation initiation. Mextli (Mxt) is an unusual 4E-BP that promotes translation by also interacting with eIF3. Here we present the crystal structures of the eIF4E-binding regions of the Drosophila melanogaster (Dm) and Caenorhabditis elegans (Ce) Mxt proteins in complex with eIF4E in the cap-bound and cap-free states. The structures reveal unexpected evolutionary plasticity in the eIF4E-binding mode, with a classical bipartite interface for Ce Mxt and a novel tripartite interface for Dm Mxt. Both interfaces comprise a canonical helix and a noncanonical helix that engage the dorsal and lateral surfaces of eIF4E, respectively. Remarkably, Dm Mxt contains a C-terminal auxiliary helix that lies anti-parallel to the canonical helix on the eIF4E dorsal surface. In contrast to the eIF4G and Ce Mxt complexes, the Dm eIF4E–Mxt complexes are resistant to competition by bipartite 4E-BPs, suggesting that Dm Mxt can bind eIF4E when eIF4G binding is inhibited. Our results uncovered unexpected diversity in the binding modes of 4E-BPs, resulting in eIF4E complexes that display differential sensitivity to 4E-BP regulation.
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spelling pubmed-45738562015-09-23 Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation Peter, Daniel Weber, Ramona Köne, Carolin Chung, Min-Yi Ebertsch, Linda Truffault, Vincent Weichenrieder, Oliver Igreja, Cátia Izaurralde, Elisa Genes Dev Research Paper The eIF4E-binding proteins (4E-BPs) are a diverse class of translation regulators that share a canonical eIF4E-binding motif (4E-BM) with eIF4G. Consequently, they compete with eIF4G for binding to eIF4E, thereby inhibiting translation initiation. Mextli (Mxt) is an unusual 4E-BP that promotes translation by also interacting with eIF3. Here we present the crystal structures of the eIF4E-binding regions of the Drosophila melanogaster (Dm) and Caenorhabditis elegans (Ce) Mxt proteins in complex with eIF4E in the cap-bound and cap-free states. The structures reveal unexpected evolutionary plasticity in the eIF4E-binding mode, with a classical bipartite interface for Ce Mxt and a novel tripartite interface for Dm Mxt. Both interfaces comprise a canonical helix and a noncanonical helix that engage the dorsal and lateral surfaces of eIF4E, respectively. Remarkably, Dm Mxt contains a C-terminal auxiliary helix that lies anti-parallel to the canonical helix on the eIF4E dorsal surface. In contrast to the eIF4G and Ce Mxt complexes, the Dm eIF4E–Mxt complexes are resistant to competition by bipartite 4E-BPs, suggesting that Dm Mxt can bind eIF4E when eIF4G binding is inhibited. Our results uncovered unexpected diversity in the binding modes of 4E-BPs, resulting in eIF4E complexes that display differential sensitivity to 4E-BP regulation. Cold Spring Harbor Laboratory Press 2015-09-01 /pmc/articles/PMC4573856/ /pubmed/26294658 http://dx.doi.org/10.1101/gad.269068.115 Text en © 2015 Peter et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Peter, Daniel
Weber, Ramona
Köne, Carolin
Chung, Min-Yi
Ebertsch, Linda
Truffault, Vincent
Weichenrieder, Oliver
Igreja, Cátia
Izaurralde, Elisa
Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation
title Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation
title_full Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation
title_fullStr Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation
title_full_unstemmed Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation
title_short Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation
title_sort mextli proteins use both canonical bipartite and novel tripartite binding modes to form eif4e complexes that display differential sensitivity to 4e-bp regulation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573856/
https://www.ncbi.nlm.nih.gov/pubmed/26294658
http://dx.doi.org/10.1101/gad.269068.115
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