title: Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation.
abstract: 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.
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Daniel
authors: D
authors: Peter
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Ramona
authors: R
authors: Weber
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Carolin
authors: C
authors: Köne
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Min-Yi
authors: MY
authors: Chung
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Linda
authors: L
authors: Ebertsch
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Vincent
authors: V
authors: Truffault
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Oliver
authors: O
authors: Weichenrieder
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Cátia
authors: C
authors: Igreja
authors: Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.
authors: Elisa
authors: E
authors: Izaurralde
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics; D004331:Drosophila melanogaster / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000502:physiology*; D014644:Genetic Variation; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D029721:Drosophila Proteins
keywords: 4E-BP; CUP; Mextli; eIF4F; eIF4G; translational regulation