Protein Translation and Folding Are Coupled by an Endoplasmic-Reticulum-Resident Kinase

Nature. 1999 Jan 21;397(6716):271-4. doi: 10.1038/16729.

Abstract

Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Cloning, Molecular
  • Endoplasmic Reticulum / enzymology*
  • Escherichia coli
  • Eukaryotic Initiation Factor-2 / chemistry
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fungal Proteins / chemistry
  • Fungal Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • Intracellular Membranes / enzymology
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Protein Biosynthesis*
  • Protein Folding*
  • Protein-Serine-Threonine Kinases*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Saccharomyces cerevisiae Proteins*
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • eIF-2 Kinase / chemistry
  • eIF-2 Kinase / genetics*
  • eIF-2 Kinase / physiology

Substances

  • Eukaryotic Initiation Factor-2
  • Fungal Proteins
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae Proteins
  • IRE1 protein, S cerevisiae
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase

Associated data

  • GENBANK/AF076681