Journal ArticleDOI
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
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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
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Journal ArticleDOI
Targeting the unfolded protein response in neurodegeneration: A new approach to therapy.
TL;DR: It is proposed that modulation of the UPR in neurodegeneration is therefore a promising target for future therapeutic treatments.
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Expression of an evolutionarily distinct novel BiP gene during the unfolded protein response in Arabidopsis thaliana.
TL;DR: Interestingly, BiP-L was substantially different from the other two Arabidopsis BiP genes in genomic organization and sequence homology, and phylogenetic analysis showed that the Bip-L protein is the most distal form among the reported plant BiP proteins.
Book ChapterDOI
Protein quality control, retention, and degradation at the endoplasmic reticulum.
TL;DR: The molecular mechanisms that are implicated and recent data that underline the importance of compartmentalization in the segregation of the various functions of the ER for their correct function are discussed.
Journal ArticleDOI
Use of a small molecule cell cycle inhibitor to control cell growth and improve specific productivity and product quality of recombinant proteins in CHO cell cultures.
Zhimei Du,David Treiber,John D. McCarter,Dina Fomina-Yadlin,Ramsey A. Saleem,Rebecca E. Mccoy,Yuling Zhang,Tharmala Tharmalingam,Matthew Leith,Brian D. Follstad,Brad Dell,Brent Grisim,Craig Zupke,Carole Heath,Arvia E. Morris,Pranhitha Reddy +15 more
TL;DR: Overall, the observations showed that cell cycle arrest by directly targeting CDK4/6 using selective inhibitor compound can be utilized consistently and rapidly to optimize process parameters, such as cell growth, qP, and glycosylation profile in recombinant antibody production cultures.
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Endoplasmic reticulum stress response in yeast and humans
TL;DR: The major advances in understanding the response to ER stress in Sc, Sp and humans are summarized and the contribution of solved protein structures to a better understanding of the UPR pathway is discussed.
References
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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.