A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1

Kimata, Yukio; Oikawa, Daisuke; Shimizu, Yusuke; Ishiwata-Kimata, Yuki; Kohno, Kenji

doi:10.1083/jcb.200405153

Cited by 254 publications

(325 citation statements)

References 40 publications

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“…Regions preceding and trailing it in the sequence are largely dispensable for regulation of Ire1, suggesting that cLD contains all necessary elements to sense unfolded proteins and transmit this information across the membrane. This result is in agreement with previous mutagenesis studies, which showed that segments can be deleted from either end of the LD without affecting its function (19,20). Second, the crystal structure of cLD defines two regions of extensive contacts at opposing ends of the monomeric cLD.…”

Section: Discussionsupporting

confidence: 82%

On the mechanism of sensing unfolded protein in the endoplasmic reticulum

Credle

Finer-Moore

Papa

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

500

473

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Unfolded proteins in the endoplasmic reticulum (ER) activate the ER transmembrane sensor Ire1 to trigger the unfolded protein response (UPR), a homeostatic signaling pathway that adjusts ER protein folding capacity according to need. Ire1 is a bifunctional enzyme, containing cytoplasmic kinase and RNase domains whose roles in signal transduction downstream of Ire1 are understood in some detail. By contrast, the question of how its ER-luminal domain (LD) senses unfolded proteins has remained an enigma. The 3.0-Å crystal structure and consequent structure-guided functional analyses of the conserved core region of the LD (cLD) leads us to a proposal for the mechanism of response. cLD exhibits a unique protein fold and is sufficient to control Ire1 activation by unfolded proteins. Dimerization of cLD monomers across a large interface creates a shared central groove formed by ␣-helices that are situated on a ␤-sheet floor. This groove is reminiscent of the peptide binding domains of major histocompatibility complexes (MHCs) in its gross architecture. Conserved amino acid side chains in Ire1 that face into the groove are shown to be important for UPR activation in that their mutation reduces the response. Mutational analyses suggest that further interaction between cLD dimers is required to form higher-order oligomers necessary for UPR activation. We propose that cLD directly binds unfolded proteins, which changes the quaternary association of the monomers in the membrane plane. The changes in the ER lumen in turn position Ire1 kinase domains in the cytoplasm optimally for autophosphorylation to initiate the UPR.Ire1 ͉ unfolded protein response ͉ MHC ͉ protein folding ͉ secretory pathway

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Section: Discussionsupporting

confidence: 82%

On the mechanism of sensing unfolded protein in the endoplasmic reticulum

Credle

Finer-Moore

Papa

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

500

473

View full text Add to dashboard Cite

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“…In addition, BiP interacts with both IRE1 and PERK and is a negative regulator of UPR activation (15,26). Although our structural studies did not identify a BiP interaction site, deletion studies in yeast and human IRE1, as well as in human PERK (17,18,27), suggest that a conserved BiP interaction site exists in the region C-terminal to residue Val-307 in human IRE1␣. It is interesting to note that the potential BiP interaction site in the crystal structure of human IRE1␣ is spatially conserved with that in the structure of yeast Ire1p (22).…”

Section: Discussionmentioning

confidence: 78%

“…However, the UPR represents a novel intracellular ER transmembrane signaling pathway, which appears to employ a ligand-independent activation mechanism (14) in which the IRE1 N-terminal luminal domain (NLD) functions as an ER stress sensor. According to this model, under normal conditions IRE1 is maintained in a monomeric state through interaction of the NLD with the ER resident chaperone BiP (15)(16)(17)(18)(19). Upon ER stress, immunoglobin-binding protein (BiP)͞glucose-regulated protein of 78 kDa (Grp78) (BiP) binds to unfolded proteins as they accumulate, permitting the released NLD to form homodimers.…”

mentioning

confidence: 99%

The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response

Zhou¹,

Liu

Back

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

319

266

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The unfolded protein response (UPR) is an evolutionarily conserved mechanism by which all eukaryotic cells adapt to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Inositolrequiring kinase 1 (IRE1) and PKR-related ER kinase (PERK) are two type I transmembrane ER-localized protein kinase receptors that signal the UPR through a process that involves homodimerization and autophosphorylation. To elucidate the molecular basis of the ER transmembrane signaling event, we determined the x-ray crystal structure of the luminal domain of human IRE1␣. The monomer of the luminal domain comprises a unique fold of a triangular assembly of ␤-sheet clusters. Structural analysis identified an extensive dimerization interface stabilized by hydrogen bonds and hydrophobic interactions. Dimerization creates an MHClike groove at the interface. However, because this groove is too narrow for peptide binding and the purified luminal domain forms high-affinity dimers in vitro, peptide binding to this groove is not required for dimerization. Consistent with our structural observations, mutations that disrupt the dimerization interface produced IRE1␣ molecules that failed to either dimerize or activate the UPR upon ER stress. In addition, mutations in a structurally homologous region within PERK also prevented dimerization. Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling. endoplasmic reticulum ͉ protein structure ͉ signal transduction ͉ protein kinase ͉ endoplasmic reticulum stress T he endoplasmic reticulum (ER) of eukaryotic cells is the cellular compartment where secretory and transmembrane proteins fold into their native conformations and undergo posttranslational modifications that are important for their structure and function. When protein folding in the ER is perturbed, a set of signal transduction pathways is activated to reduce the proteinfolding load and increase folding capacity. These pathways are collectively termed the unfolded protein response (UPR) (1-4). To increase the folding capacity, synthesis of ER resident chaperones and folding catalysts is induced. To decrease the folding load in the ER, global mRNA translation is attenuated and clearance of misfolded proteins through ER-associated degradation is increased. UPR signaling is mediated by three ER resident transmembrane proteins: IRE1, PERK, and ATF6.IRE1 is a type I transmembrane protein kinase receptor that also has a site-specific RNase activity that, upon activation, initiates a site-specific unconventional splicing reaction (5, 6). The substrate for IRE1 RNase in metazoans is Xbp1 mRNA, which encodes a basic leucine zipper transcription factor of the ATF͞CREB family. XBP1 controls expression of genes containing an X-box element or a UPR element in their promoter regions (7-10). The IRE1-mediated splicing reaction introduces into XBP1 an alternative C terminus, thereby generating an X...

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“…Few methods exist to assess global changes in misfolded protein accumulation. Biochemical techniques such as BiP/Kar2 sedimentation have been used to quantitate the chaperone binding to misfolded substrates [80]. However, until recently, no option was available for imaging intact cells.…”

Section: Approaches For Imaging Er Stress and Upr Activity In Livinmentioning

confidence: 99%

Approaches to imaging unfolded secretory protein stress in living cells

Lajoie

Fazio

Snapp

2014

Endoplasmic Reticulum Stress in Diseases

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The endoplasmic reticulum (ER) is the point of entry of proteins into the secretory pathway. Nascent peptides interact with the ER quality control machinery that ensures correct folding of the nascent proteins. Failure to properly fold proteins can lead to loss of protein function and cytotoxic aggregation of misfolded proteins that can lead to cell death. To cope with increases in the ER unfolded secretory protein burden, cells have evolved the Unfolded Protein Response (UPR). The UPR is the primary signaling pathway that monitors the state of the ER folding environment. When the unfolded protein burden overwhelms the capacity of the ER quality control machinery, a state termed ER stress, sensor proteins detect accumulation of misfolded peptides and trigger the UPR transcriptional response. The UPR, which is conserved from yeast to mammals, consists of an ensemble of complex signaling pathways that aims at adapting the ER to the new misfolded protein load. To determine how different factors impact the ER folding environment, various tools and assays have been developed. In this review, we discuss recent advances in live cell imaging reporters and model systems that enable researchers to monitor changes in the unfolded secretory protein burden and activation of the UPR and its associated signaling pathways.

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A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1

Cited by 254 publications

References 40 publications

On the mechanism of sensing unfolded protein in the endoplasmic reticulum

On the mechanism of sensing unfolded protein in the endoplasmic reticulum

The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response

Approaches to imaging unfolded secretory protein stress in living cells

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