Molecular architecture of 4E-BP translational inhibitors bound to eIF4E

Daniel Peter; Cátia Igreja; Ramona Weber; Lara Wohlbold; Catrin Weiler; Linda Ebertsch; Oliver Weichenrieder; Elisa Izaurralde

doi:10.1016/j.molcel.2015.01.017

Molecular architecture of 4E-BP translational inhibitors bound to eIF4E

Mol Cell. 2015 Mar 19;57(6):1074-1087. doi: 10.1016/j.molcel.2015.01.017. Epub 2015 Feb 19.

Authors

Daniel Peter¹, Cátia Igreja¹, Ramona Weber¹, Lara Wohlbold¹, Catrin Weiler¹, Linda Ebertsch¹, Oliver Weichenrieder², Elisa Izaurralde³

Affiliations

¹ Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
² Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: [email protected].
³ Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address: [email protected].

PMID: 25702871
DOI: 10.1016/j.molcel.2015.01.017

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / chemistry*
Adaptor Proteins, Signal Transducing / metabolism
Amino Acid Motifs
Animals
Binding Sites
Binding, Competitive
Carrier Proteins / chemistry
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Cycle Proteins
Crystallography, X-Ray
Drosophila Proteins / chemistry*
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Eukaryotic Initiation Factor-4E / chemistry*
Eukaryotic Initiation Factor-4E / metabolism*
Eukaryotic Initiation Factor-4G / chemistry*
Eukaryotic Initiation Factor-4G / metabolism
Humans
Intracellular Signaling Peptides and Proteins / chemistry*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Models, Molecular
Molecular Mimicry
Peptide Initiation Factors / chemistry*
Peptide Initiation Factors / genetics
Peptide Initiation Factors / metabolism
Phosphoproteins / chemistry*
Phosphoproteins / metabolism
Phosphorylation
Protein Conformation
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Cell Cycle Proteins
Drosophila Proteins
EIF4EBP1 protein, human
EIF4EBP3 protein, human
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factor-4G
Intracellular Signaling Peptides and Proteins
Peptide Initiation Factors
Phosphoproteins
Recombinant Proteins
Thor protein, Drosophila
eIF4G2 protein, Drosophila

Associated data

PDB/4UE8
PDB/4UE9
PDB/4UEA
PDB/4UEB
PDB/4UEC
PDB/4UED