Journal ArticleDOI
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
Reads0
Chats0
TLDR
The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.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.read more
Citations
More filters
Journal ArticleDOI
eIF2B-Related Disorders: Antenatal Onset and Involvement of Multiple Organs.
Marjo S. van der Knaap,Carola G.M. van Berkel,Jochen Herms,Rudy Van Coster,Martina Baethmann,Sakkubai Naidu,Eugen Boltshauser,Michèl A.A.P. Willemsen,Barbara Plecko,Georg F. Hoffmann,Christopher G. Proud,Gert C. Scheper,Jan C. Pronk +12 more
TL;DR: Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.
Journal ArticleDOI
Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury.
Gavin C Higgins,Philip M Beart,Yea Seul Shin,Minghui Jessica Chen,Nam Sang Cheung,Phillip Nagley +5 more
TL;DR: Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse modes of cell death mediated by mitochondria under oxidative stress.
Journal ArticleDOI
Endoplasmic reticulum stress in beta-cells and development of diabetes
TL;DR: The underlying molecular mechanisms of ER-stress-mediated beta-cell dysfunction and death during the progression of diabetes are outlined.
Journal ArticleDOI
Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death
TL;DR: The current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling are discussed, which may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection.
Journal ArticleDOI
PERK (eIF2α kinase) is required to activate the stress-activated MAPKs and induce the expression of immediate-early genes upon disruption of ER calcium homoeostasis
TL;DR: It is suggested that this specificity ofPERK function in the UPR is an extension of the normal physiological function of PERK to act as a calcium sensor in the ER.
References
More filters
Journal ArticleDOI
Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
Caroline E. Shamu,Peter Walter +1 more
TL;DR: Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.
Journal ArticleDOI
Protein folding in the cell.
TL;DR: Folding and assembly of polypeptides in vivo involves other proteins, many of which belong to families that have been highly conserved during evolution.
Journal ArticleDOI
The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins
TL;DR: Testing the hypothesis that the presence of malfolded proteins may be the primary signal for induction of GRPs by expressing wild-type and mutant forms of influenza virus haemagglutinin in simian cells shows that malfoldingper se, rather than abnormal glycosylation1, is the proximal inducer of this family of stress proteins.
Journal ArticleDOI
Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase
TL;DR: IRE1 encodes a transmembrane serine/threonine kinase that it is proposed transmits the unfolded protein signal across the ER or inner nuclear membrane, suggesting that the induction of ER resident proteins is coupled to the biogenesis of new ER membrane.
Journal ArticleDOI
A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells
TL;DR: HIre1p is an essential proximal sensor of the unfolded protein response pathway in mammalian cells and is demonstrated to be highly conserved to the yeast counterpart having a Ser/Thr protein kinase domain and a domain homologous to RNase L.