<i>N</i>‐Glycan‐based <scp>ER</scp> Molecular Chaperone and Protein Quality Control System: The Calnexin Binding Cycle

Lamriben, Lydia; Graham, Jill B.; Adams, Benjamin M.; Hebert, Daniel N.

doi:10.1111/tra.12358

Cited by 154 publications

(122 citation statements)

References 155 publications

(214 reference statements)

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“…TNM induces endoplasmic reticulum stress via inhibition of protein N-glycosylation in the endoplasmic reticulum, which is part of the cell´s protein quality control mechanisms (Lamriben et al 2016). Its mechanism of action is based on inhibition of N-acetyl glucosamine transfer from UDP-N-acetyl glucosamine to dolichol phosphate (Heifetz et al 1979) attached to the inner side of the endoplasmic reticulum Figure 1.…”

Section: Introductionmentioning

confidence: 99%

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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Abstract. In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/ VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides.

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Section: Introductionmentioning

confidence: 99%

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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“…During transit through the secretory pathway, all three glucose residues and six of nine mannose residues are trimmed, and the structures are extended further by Golgi glycosyltransferases to generate the diverse collection of complex-type glycans found on cell-surface and secreted glycoproteins (2). The transiently formed glycanprocessing intermediates resulting from glucose and mannose cleavage also play critical roles in the early secretory pathway, including acting as ligands for ER chaperones, signals for ER quality control and ER-associated degradation (ERAD), and targeting signals during intracellular transport (3)(4)(5)(6).…”

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confidence: 99%

Substrate recognition and catalysis by GH47 α-mannosidases involved in Asn-linked glycan maturation in the mammalian secretory pathway

Xiang

Karaveg

Moremen

2016

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

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Maturation of Asn-linked oligosaccharides in the eukaryotic secretory pathway requires the trimming of nascent glycan chains to remove all glucose and several mannose residues before extension into complex-type structures on the cell surface and secreted glycoproteins. Multiple glycoside hydrolase family 47 (GH47) α-mannosidases, including endoplasmic reticulum (ER) α-mannosidase I (ERManI) and Golgi α-mannosidase IA (GMIA), are responsible for cleavage of terminal α1,2-linked mannose residues to produce uniquely trimmed oligomannose isomers that are necessary for ER glycoprotein quality control and glycan maturation. ERManI and GMIA have similar catalytic domain structures, but each enzyme cleaves distinct residues from tribranched oligomannose glycan substrates. The structural basis for branch-specific cleavage by ERManI and GMIA was explored by replacing an essential enzyme-bound Ca 2+ ion with a lanthanum (La 3+) ion. This ion swap led to enzyme inactivation while retaining high-affinity substrate interactions. Cocrystallization of La 3+ -bound enzymes with Man 9 GlcNAc 2 substrate analogs revealed enzyme-substrate complexes with distinct modes of glycan branch insertion into the respective enzyme active-site clefts. Both enzymes had glycan interactions that extended across the entire glycan structure, but each enzyme engaged a different glycan branch and used different sets of glycan interactions. Additional mutagenesis and time-course studies of glycan cleavage probed the structural basis of enzyme specificity. The results provide insights into the enzyme catalytic mechanisms and reveal structural snapshots of the sequential glycan cleavage events. The data also indicate that full steric access to glycan substrates determines the efficiency of mannose-trimming reactions that control the conversion to complex-type structures in mammalian cells.Asn-linked glycan processing | α-mannosidase | glycosidase mechanism | glycoside hydrolase | bioinorganic chemistry

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“…This has been observed in many studies using glucosidase-deficient or castanospermine-treated cells (1,2,13,22,46). Another recent example comes from the experiment of Wijeyesakere et al (22) noted above.…”

Section: Discussionmentioning

confidence: 71%

Contributions of the Lectin and Polypeptide Binding Sites of Calreticulin to Its Chaperone Functions in Vitro and in Cells

Lum

Ahmad

Hong

et al. 2016

Journal of Biological Chemistry

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Calreticulin is a lectin chaperone of the endoplasmic reticulum that interacts with newly synthesized glycoproteins by binding to Glc 1 Man 9 GlcNAc 2 oligosaccharides as well as to the polypeptide chain. In vitro, the latter interaction potently suppresses the aggregation of various non-glycosylated proteins. Although the lectin-oligosaccharide association is well understood, the polypeptide-based interaction is more controversial because the binding site on calreticulin has not been identified, and its significance in the biogenesis of glycoproteins in cells remains unknown. In this study, we identified the polypeptide binding site responsible for the in vitro aggregation suppression function by mutating four candidate hydrophobic surface patches. Mutations in only one patch, P19K/I21E and Y22K/ F84E, impaired the ability of calreticulin to suppress the thermally induced aggregation of non-glycosylated firefly luciferase. These mutants also failed to bind several hydrophobic peptides that act as substrate mimetics and compete in the luciferase aggregation suppression assay. To assess the relative contributions of the glycan-dependent and -independent interactions in living cells, we expressed lectin-deficient, polypeptide bindingdeficient, and doubly deficient calreticulin constructs in calreticulin-negative cells and monitored the effects on the biogenesis of MHC class I molecules, the solubility of mutant forms of ␣ 1 -antitrypsin, and interactions with newly synthesized glycoproteins. In all cases, we observed a profound impairment in calreticulin function when its lectin site was inactivated. Remarkably, inactivation of the polypeptide binding site had little impact. These findings indicate that the lectin-based mode of client interaction is the predominant contributor to the chaperone functions of calreticulin within the endoplasmic reticulum. Membrane-bound calnexin (Cnx)3 and its soluble paralog calreticulin (Crt) are glycoprotein-specific chaperones of the endoplasmic reticulum (ER). As components of the ER quality control system, they retain glycoprotein folding intermediates within this organelle and assist folding by preventing aggregation and by recruiting folding catalysts such as the thiol oxidoreductase ERp57 and peptidyl-prolyl isomerase cyclophilin B (for reviews, see Refs. 1 and 2). Both chaperones consist of a globular lectin domain and an extended arm or P domain (3-5) with the tip of the arm domain comprising the binding site for ERp57 (6) and cyclophilin B (7). The specificity for glycoproteins resides within their lectin domains, which recognize a monoglucosylated oligosaccharide-processing intermediate of composition Glc 1 Man 9 GlcNAc 2 (8 -10). Cycles of chaperone binding and release are regulated by the availability of the terminal glucose residue on this oligosaccharide with glucose removal catalyzed by glucosidase II and its readdition by UDPglucose:glycoprotein glucosyltransferase I (11). UDP-glucose: glycoprotein glucosyltransferase I acts as the folding sensor in the cycle, only...

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N‐Glycan‐based ER Molecular Chaperone and Protein Quality Control System: The Calnexin Binding Cycle

Cited by 154 publications

References 155 publications

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Substrate recognition and catalysis by GH47 α-mannosidases involved in Asn-linked glycan maturation in the mammalian secretory pathway

Contributions of the Lectin and Polypeptide Binding Sites of Calreticulin to Its Chaperone Functions in Vitro and in Cells

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