Journal Article

eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation

Cate, Jamie H. D., Kranzusch, Philip J., Doudna, Jennifer A., Lee, Amy S. Y.

2016

Overview

The initiation protein eIF3d serves as an alternative cap-recognition factor for a subclass of mRNAs, such as c-Jun; the high-resolution structure of the eIF3d cap-binding domain can be modelled onto the cap structure, defining interactions that are needed for translation of these mRNAs. An alternative 5′ mRNA capping pathway Recruitment of the ribosome to eukaryotic messenger RNAs (mRNAs) involves interaction between the translation initiation factor, eIF4E, and a specialized nucleotide, or 'cap', at the 5′ end of the mRNA. eIF4E is inactivated under certain conditions, but translation of numerous mRNAs is maintained. Jamie Cate and colleagues describe how another initiation protein, eIF3d, serves as an alternative cap-recognition factor for a subclass of mRNAs, such as c-Jun . The high-resolution structure of the eIF3d cap-binding domain can be modelled onto the cap structure, defining interactions that are needed for translation of these mRNAs. They also find that c-Jun mRNA contains an element that inhibits eIF4E recruitment. Eukaryotic mRNAs contain a 5′ cap structure that is crucial for recruitment of the translation machinery and initiation of protein synthesis. mRNA recognition is thought to require direct interactions between eukaryotic initiation factor 4E (eIF4E) and the mRNA cap. However, translation of numerous capped mRNAs remains robust during cellular stress, early development, and cell cycle progression 1 despite inactivation of eIF4E. Here we describe a cap-dependent pathway of translation initiation in human cells that relies on a previously unknown cap-binding activity of eIF3d, a subunit of the 800-kilodalton eIF3 complex. A 1.4 Å crystal structure of the eIF3d cap-binding domain reveals unexpected homology to endonucleases involved in RNA turnover, and allows modelling of cap recognition by eIF3d. eIF3d makes specific contacts with the cap, as exemplified by cap analogue competition, and these interactions are essential for assembly of translation initiation complexes on eIF3-specialized mRNAs 2 such as the cell proliferation regulator c-Jun (also known as JUN ). The c-Jun mRNA further encodes an inhibitory RNA element that blocks eIF4E recruitment, thus enforcing alternative cap recognition by eIF3d. Our results reveal a mechanism of cap-dependent translation that is independent of eIF4E, and illustrate how modular RNA elements work together to direct specialized forms of translation initiation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 38/22 / 38/90 / 631/337/574 / 631/45/500 / 631/45/535 / 82/29 / 82/58 / 82/83 / Analysis / Binding proteins / Binding, Competitive / Cell growth / Chemical properties / Crystallography, X-Ray / Eukaryotic Initiation Factor-3 - chemistry / Eukaryotic Initiation Factor-3 - metabolism / Eukaryotic Initiation Factor-4E - antagonists & inhibitors / Eukaryotic Initiation Factor-4E - metabolism / Eukaryotic Initiation Factor-4F - antagonists & inhibitors / Eukaryotic Initiation Factor-4F - metabolism / Genes, jun - genetics / Genetic translation / Humanities and Social Sciences / Humans / Inactivation / letter / Messenger RNA / Models, Molecular / multidisciplinary / Peptide Chain Initiation, Translational / Phylogeny / Protein Binding / Protein biosynthesis / Protein Structure, Tertiary / Protein Subunits - chemistry / Protein Subunits - metabolism / Protein synthesis / Proteins / Ribonucleic acid / RNA / RNA Caps - chemistry / RNA Caps - genetics / RNA Caps - metabolism / RNA-Binding Proteins - chemistry / RNA-Binding Proteins - metabolism / Science