Translational initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition

Author:

Llácer Jose Luis12ORCID,Hussain Tanweer3,Saini Adesh K4ORCID,Nanda Jagpreet Singh5ORCID,Kaur Sukhvir4,Gordiyenko Yuliya1,Kumar Rakesh4,Hinnebusch Alan G6,Lorsch Jon R5ORCID,Ramakrishnan V1

Affiliation:

1. MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

2. Instituto de Biomedicina de Valencia (IBV-CSIC), Valencia, Spain

3. Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India

4. Shoolini University of Biotechnology and Management Sciences, Himachal Pradesh, India

5. Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice K Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

6. Laboratory of Gene Regulation and Development, Eunice K Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Abstract

In eukaryotic translation initiation, AUG recognition of the mRNA requires accommodation of Met-tRNAi in a ‘PIN’ state, which is antagonized by the factor eIF1. eIF5 is a GTPase activating protein (GAP) of eIF2 that additionally promotes stringent AUG selection, but the molecular basis of its dual function was unknown. We present a cryo-electron microscopy (cryo-EM) reconstruction of a yeast 48S pre-initiation complex (PIC), at an overall resolution of 3.0 Å, featuring the N-terminal domain (NTD) of eIF5 bound to the 40S subunit at the location vacated by eIF1. eIF5 interacts with and allows a more accommodated orientation of Met-tRNAi. Substitutions of eIF5 residues involved in the eIF5-NTD/tRNAi interaction influenced initiation at near-cognate UUG codonsin vivo, and the closed/open PIC conformation in vitro, consistent with direct stabilization of the codon:anticodon duplex by the wild-type eIF5-NTD. The present structure reveals the basis for a key role of eIF5 in start-codon selection.

Funder

Department of Science and Technology, Ministry of Science and Technology

Human Frontier Science Program

National Institutes of Health

Medical Research Council

Wellcome Trust

Agouron Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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