Chaperone Function of Hgh1 in the Biogenesis of Eukaryotic Elongation Factor 2

Mol Cell. 2019 Apr 4;74(1):88-100.e9. doi: 10.1016/j.molcel.2019.01.034. Epub 2019 Mar 12.

Abstract

Eukaryotic elongation factor 2 (eEF2) is an abundant and essential component of the translation machinery. The biogenesis of this 93 kDa multi-domain protein is assisted by the chaperonin TRiC/CCT. Here, we show in yeast cells that the highly conserved protein Hgh1 (FAM203 in humans) is a chaperone that cooperates with TRiC in eEF2 folding. In the absence of Hgh1, a substantial fraction of newly synthesized eEF2 is degraded or aggregates. We solved the crystal structure of Hgh1 and analyzed the interaction of wild-type and mutant Hgh1 with eEF2. These experiments revealed that Hgh1 is an armadillo repeat protein that binds to the dynamic central domain III of eEF2 via a bipartite interface. Hgh1 binding recruits TRiC to the C-terminal eEF2 module and prevents unproductive interactions of domain III, allowing efficient folding of the N-terminal GTPase module. eEF2 folding is completed upon dissociation of TRiC and Hgh1.

Keywords: armadillo repeat; chaperonin; crystal structure; hydrogen-deuterium exchange; molecular chaperone; protein folding; protein translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Molecular
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Peptide Elongation Factor 2 / chemistry
  • Peptide Elongation Factor 2 / genetics
  • Peptide Elongation Factor 2 / metabolism*
  • Protein Binding
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Structure-Activity Relationship

Substances

  • HGH1 protein, S cerevisiae
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Peptide Elongation Factor 2
  • Saccharomyces cerevisiae Proteins