The Crystal Structure of Yeast Protein Disulfide Isomerase Suggests Cooperativity between Its Active Sites

Geng, Tao; Xiang, Song; Noiva, Robert; Lennarz, William J.; Schindelin, Hermann

doi:10.1016/j.cell.2005.10.044

Cited by 359 publications

(402 citation statements)

References 56 publications

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“…ERp27 possesses a substrate-binding site very similar to that found in human PDI (43), yeast PDI (44), and ERp44 (45) which, however, is blocked by a network of salt bridges in ERp57 (46) and ERp72 (47). It is therefore highly likely that both PDI and ERp44 also possess the ability to distinguish between the folded and unfolded state of potential substrates as has been demonstrated for ERp27.…”

Section: Discussionmentioning

confidence: 88%

The Crystal Structure of the Protein-Disulfide Isomerase Family Member ERp27 Provides Insights into Its Substrate Binding Capabilities

Kober¹,

Koelmel²,

Kuper

et al. 2013

Journal of Biological Chemistry

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Background: ERp27 is a redox-inactive member of the protein-disulfide isomerase family. Results: The crystal structure of ERp27 reveals how the substrate-binding site can be modulated by conformational changes. Conclusion: ERp27 is induced during ER stress and binds misfolded proteins. Significance: ERp27 may act as a safety overflow under stress conditions, funneling excess misfolded protein onto ERp57.

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Section: Discussionmentioning

confidence: 88%

The Crystal Structure of the Protein-Disulfide Isomerase Family Member ERp27 Provides Insights into Its Substrate Binding Capabilities

Kober¹,

Koelmel²,

Kuper

et al. 2013

Journal of Biological Chemistry

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“…The experimental system PDI contains 5 N-glycosylation sites (N82/N117/N155/ N174/N425, numbered according to full-length PDI protein) (43). We transiently expressed secreted (without HDEL retrieval sequence) and the ER-retained form of PDI (with the HDEL retrieval sequence), respectively, called secreted Sec-PDI and ER-PDI (16), in Freestyle CHO-S cells.…”

Section: Resultsmentioning

confidence: 99%

Influence of protein/glycan interaction on site‐specific glycan heterogeneity

Losfeld¹,

Scibona²,

Lin³

et al. 2017

FASEB j.

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To study how the interaction between N-linked glycans and the surrounding amino acids influences oligosaccharide processing, we used protein disulfide isomerase (PDI), a glycoprotein bearing 5 N-glycosylation sites, as a model system and expressed it transiently in a Chinese hamster ovary (CHO)-S cell line. PDI was produced as both secreted Sec-PDI and endoplasmic reticulum-retained glycoprotein (ER)-PDI, to study glycan processing by ER and Golgi resident enzymes. Quantitative site-specific glycosylation profiles were obtained, and flux analysis enabled modeling site-specific glycan processing. By altering the primary sequence of PDI, we changed the glycan/ protein interaction and thus the site-specific glycoprofile because of the improved enzymatic fluxes at enzymatic bottlenecks. Our results highlight the importance of direct interactions between N-glycans and surface-exposed amino acids of glycoproteins on processing in the ER and the Golgi and the possibility of changing a site-specific N-glycan profile by modulating such interactions and thus the associated enzymatic fluxes. Altering the primary protein sequence can therefore be used to glycoengineer recombinant proteins.-Losfeld, M.-E., Scibona, E., Lin, C.-W., Villiger, T. K., Gauss, R., Morbidelli, M., Aebi, M. Influence of protein/glycan interaction on site-specific glycan heterogeneity. FASEB J. 31, 4623-4635 (2017). www.fasebj.org KEY WORDS: glycoengineering • glycobiology • glycoprotein maturation • Golgi processing • enzymatic flux N-glycosylation is a major posttranslational modification of proteins that modulates folding, maturation, trafficking, and secretion, as well as specific protein functions (1-3). Contrary to many other posttranslational modifications, N-glycans are composed of many monosaccharide units, creating a large diversity of glycan structures (4, 5). In eukaryotic cells, the N-glycosylation occurs in the endoplasmic reticulum (ER) after a conserved pathway. The oligosaccharide GlcNAc 2 Man 9 Glc 3 is assembled on the lipid dolicholpyrophosphate at the membrane of the ER and then is covalently linked to the side-chain amide of the asparagine residue in the sequon N-X-S/T by oligosaccharyltransferase (OST) (1, 6, 7). Multiple sites on one glycoprotein can be modified by the OST complex and with the increasing complexity of multicellular organism, an increasing number of N-glycosylation sites in the glycoproteome are observed. It is estimated that up to 6000 different sites are modified by OST in mammalian cells (8). In the second phase of the N-glycosylation pathway, the protein-linked glycan is trimmed by glucosidases and mannosidases (1, 9) and is subsequently modified by different glycosyltransferases spatially distributed along the secretory pathway. N-glycan processing enzymes have defined substrate specificities and locations in the secretory pathway (9, 10), and their expression level can be regulated upon internal and external signals.Glycan maturation in the secretory pathway is not a template-driven process. The...

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“…Enzyme-catalysed oxidative folding in other compartments such as the bacterial periplasm or the ER is well understood 4,[18][19][20][21] . It involves complex systems of thiol-disulphide oxidoreductases that use thioredoxin-like domains for introducing disulphides into folding protein chains and for isomerizing incorrect disulphides that form preferentially early in folding.…”

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confidence: 99%

Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

Koch

Schmid

2014

Nat Commun

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Mia40 catalyses the oxidative folding of disulphide-containing proteins in the mitochondria. The folding pathway is directed by the formation of the first mixed disulphide between Mia40 and its substrate. Here, we employ Cox17 to elucidate the molecular determinants of this reaction. Mia40 engages initially in a dynamic non-covalent enzyme-substrate complex that forms and dissociates within milliseconds. Cys36 of Cox17 forms the mixed disulphide in an extremely rapid reaction that is limited by the preceding complex formation with Mia40. Cys36 reacts much faster than the three other cysteines of Cox17, because it neighbours three hydrophobic residues. Mia40 binds preferentially to hydrophobic regions and the dynamic nature of the non-covalent complex allows rapid reorientation for an optimal positioning of the reactive cysteine. Mia40 thus uses the unique proximity between its substrate-binding site and the catalytic disulphide to select a particular cysteine for forming the critical initial mixed disulphide.

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The Crystal Structure of Yeast Protein Disulfide Isomerase Suggests Cooperativity between Its Active Sites

Cited by 359 publications

References 56 publications

The Crystal Structure of the Protein-Disulfide Isomerase Family Member ERp27 Provides Insights into Its Substrate Binding Capabilities

The Crystal Structure of the Protein-Disulfide Isomerase Family Member ERp27 Provides Insights into Its Substrate Binding Capabilities

Influence of protein/glycan interaction on site‐specific glycan heterogeneity

Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

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