Structural and Functional Insights into Human Re-initiation Complexes

Mol Cell. 2017 Aug 3;67(3):447-456.e7. doi: 10.1016/j.molcel.2017.06.032. Epub 2017 Jul 18.


After having translated short upstream open reading frames, ribosomes can re-initiate translation on the same mRNA. This process, referred to as re-initiation, controls the translation of a large fraction of mammalian cellular mRNAs, many of which are important in cancer. Key ribosomal binding proteins involved in re-initiation are the eukaryotic translation initiation factor 2D (eIF2D) or the homologous complex of MCT-1/DENR. We determined the structures of these factors bound to the human 40S ribosomal subunit in complex with initiator tRNA positioned on an mRNA start codon in the P-site using a combination of cryoelectron microscopy and X-ray crystallography. The structures, supported by biochemical experiments, reveal how eIF2D emulates the function of several canonical translation initiation factors by using three independent, flexibly connected RNA binding domains to simultaneously monitor codon-anticodon interactions in the ribosomal P-site and position the initiator tRNA.

Keywords: DENR; MCT-1; eIF2D; initiator tRNA; ligatin; ribosomal recycling; start codon recognition; translation initiation; translation re-initiation; translation regulation.

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Eukaryotic Initiation Factor-2 / chemistry
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Eukaryotic Initiation Factors / chemistry
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Multiprotein Complexes
  • Mutation
  • Nucleic Acid Conformation
  • Oncogene Proteins / chemistry
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Protein Binding
  • Protein Conformation
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA, Transfer / chemistry
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism*
  • Ribosome Subunits, Small, Eukaryotic / chemistry
  • Ribosome Subunits, Small, Eukaryotic / genetics
  • Ribosome Subunits, Small, Eukaryotic / metabolism*
  • Structure-Activity Relationship
  • Transcription Initiation Site*
  • Transcription Initiation, Genetic*
  • Transfection


  • Cell Cycle Proteins
  • DENR protein, human
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factors
  • MCTS1 protein, human
  • Multiprotein Complexes
  • Oncogene Proteins
  • RNA, Messenger
  • eIF2D protein, human
  • RNA, Transfer