Ca2+ Regulation of Interactions between Endoplasmic Reticulum Chaperones

Corbett, Elaine F.; Oikawa, Kimio; François, Patrice; Tessier, Daniel C.; Kay, Cyril M.; Bergeron, John J.M.; Thomas, David Y.; Krause, Karl‐Heinz; Michalak, Marek

doi:10.1074/jbc.274.10.6203

Cited by 196 publications

(142 citation statements)

References 53 publications

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“…However, it remains still unclear whether and, if so, how eminent Ca 2+ fluctuations faced by the ER under physiological conditions due to regular cell stimulation [2,3,15] influence ER chaperone activity [8]. Additionally, since mitochondria are of pivotal importance to direct entering Ca 2+ towards the ER for its refilling [15], the contribution of such mitochondrial Ca 2+ transfer to Ca 2+ -dependent protein maturation in the ER needs to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Initially characterized as Ca 2+ -binding protein of the sarcoplasmic reticulum [6], conformation [7], chaperone interactions [8] and thus activity of calreticulin have been shown to be directly affected by [Ca 2+ ] ER (free ER Ca 2+ concentration). A decrease in ambient [Ca 2+ ] renders the calreticulin cycle and associated folding catalysts, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…protein disulphide-isomerase and ERp57, inactive [9]. However, these principles of Ca 2+ -dependent protein folding have been assessed mainly on recombinant proteins [7,8,10] or by artificially applying excessive ER stress [11][12][13], while a detailed analysis of its kinetics and correlation with physiological Ca 2+ fluctuations are lacking. While there are studies that address this issue [14], it still remains questionable whether the ER protein-folding machinery is influenced by spatial and temporal dynamics of [Ca 2+ ] ER in intact cells and, if so, how efficient protein folding is maintained under physiological cell stimulation.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum

Osibow

Frank

Malli

et al. 2006

Biochemical Journal

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Considering the physiological Ca 2+ dynamics within the ER (endoplasmic reticulum), it remains unclear how efficient protein folding is maintained in living cells. Thus, utilizing the strictly folding-dependent activity and secretion of LPL (lipoprotein lipase), we evaluated the impact of ER Ca 2+ content and mitochondrial contribution to Ca 2+ -dependent protein folding. Exhaustive ER Ca 2+ depletion by inhibition of sarcoplasmic/ endoplasmic reticulum Ca 2+ -ATPases caused strong, but reversible, reduction of cell-associated and released activity of constitutive and adenovirus-encoded human LPL in CHO-K1 (Chinesehamster ovary K1) and endothelial cells respectively, which was not due to decline of mRNA or intracellular protein levels. In contrast, stimulation with the IP 3 (inositol 1,4,5-trisphosphate)-generating agonist histamine only moderately and transiently affected LPL maturation in endothelial cells that paralleled a basically preserved ER Ca 2+ content. However, in the absence of extracellular Ca 2+ or upon prevention of transmitochondrial Ca 2+ flux, LPL maturation discontinued upon histamine stimulation. Collectively, these data indicate that Ca 2+ -dependent protein folding in the ER is predominantly controlled by intraluminal Ca 2+ and is largely maintained during physiological cell stimulation owing to efficient ER Ca 2+ refilling. Since Ca 2+ entry and mitochondrial Ca 2+ homoeostasis are crucial for continuous Ca 2+ -dependent protein maturation in the ER, their pathological alterations may result in dysfunctional protein folding.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum

Osibow

Frank

Malli

et al. 2006

Biochemical Journal

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“…The N domain (residues 1-180), also known as vasostatin, is extremely conserved among calreticulins from different species [13]. The N domain interacts with the DNA-binding domain of the glucocorticoid receptor in vitro [14], with rubella virus RNA [15], with α-integrin [16], and with protein disulphide-isomerase (PDI) and ER protein 57 (ERp57) [17]. The N domain of calreticulin also inhibits proliferation of endothelial cells and suppresses angiogenesis [10].…”

Section: Introductionmentioning

confidence: 99%

“…The P domain is thought to be critical for the lectin-like chaperone activity of calreticulin [19]. The P domain of calreticulin also interacts with PDI [17] and perforin [20,21]. The Cterminal region of the protein is highly acidic and terminates with the KDEL ER retrieval sequence [22].…”

Section: Introductionmentioning

confidence: 99%

Characterization of DNA vaccines encoding the domains of calreticulin for their ability to elicit tumor-specific immunity and antiangiogenesis

Cheng

Hung

Chen

et al. 2005

Vaccine

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Antigen-specific cancer immunotherapy and antiangiogenesis are feasible strategies for cancer therapy because they can potentially treat systemic tumors at multiple sites in the body while discriminating between neoplastic and non-neoplastic cells. We have previously developed a DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus-16 E7 and have found that this vaccine generates strong E7-specific antitumor immunity and antiangiogenic effects in vaccinated mice. In this study, we characterized the domains of CRT to produce E7-specific antitumor immunity and antiangiogenic effects by generating DNA vaccines encoding each of the three domains of CRT (N, P, and C domains) linked to the HPV-16 E7 antigen. We found that C57BL/6 mice vaccinated intradermally with DNA encoding the N domain of CRT (NCRT), the P domain of CRT (PCRT), or the C domain of CRT (CCRT) linked with E7 exhibited significant increases in E7-specific CD8 + T cell precursors and impressive antitumor effects against E7-expressing tumors compared to mice vaccinated with wild-type E7 DNA. In addition, the N domain of CRT also showed antiangiogenic properties that might have contributed to the antitumor effect of NCRT/E7. Thus, the N domain of CRT can be linked to a tumor antigen in a DNA vaccine to generate both antigen-specific immunity and antiangiogenic effects for cancer therapy.

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Calnexin, Calreticulin and Glycoprotein Folding Within the Endoplasmic Reticulum

Leach¹,

Williams²,

Ernst

et al. 2000

Carbohydrates in Chemistry and Biology

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Proteins destined for secretion or for various locations along the secretory pathway are initially translocated wholly or in part into the endoplasmic reticulum (ER). Within this compartment the vast majority of proteins are glycosylated at Asn residues with a preassembled oligosaccharide of structure Glc3MangGlcNAc2. These Asn-linked glycoproteins subsequently fold and assemble with the aid of a diverse array of protein folding catalysts and molecular chaperones. The protein folding catalysts include the thiol oxidoreductases protein disulfide isomerase (PDI), ERp57, and ERp72, that catalyze the formation and reshuffling of disulfide bonds, as well as peptidyl prolyl isomerases that catalyze the interconversion between cis and trans forms of peptide bonds preceding proline residues. By contrast, molecular chaperones enhance the efficiency of protein folding by binding transiently to hydrophobic segments of folding intermediates thereby preventing the formation of irreversible aggregates. Molecular chaperones of the ER also participate in a process termed quality control in which their interactions cause non-native proteins to be retained in this organelle either until they are degraded or until a native conformation is attained. Multiple molecular chaperones reside within the ER, including Grp94, a member of the HSP90 family of heat shock proteins, and BiP, an HSP70 family member. In addition, two other molecular chaperones, calnexin and calreticulin, appear to have evolved specifically to participate in the biogenesis of Asnlinked glycoproteins. In this review, we discuss the molecular basis for the glycoprotein specificity of these unique chaperones, their structural and functional relationship, current models for their mechanism of action, and their interplay with other ER chaperones. Structure and Properties of Calnexin and CalreticulinCalnexin, calreticulin, and the testis-specific homolog calmegin constitute a family of abundant ER proteins. Calnexin is a type I transmembrane protein that is pres-

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Ca2+ Regulation of Interactions between Endoplasmic Reticulum Chaperones

Cited by 196 publications

References 53 publications

Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum

Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum

Characterization of DNA vaccines encoding the domains of calreticulin for their ability to elicit tumor-specific immunity and antiangiogenesis

Calnexin, Calreticulin and Glycoprotein Folding Within the Endoplasmic Reticulum

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