Substrate Specificity of the Oxidoreductase ERp57 Is Determined Primarily by Its Interaction with Calnexin and Calreticulin

The formation of disulfides within proteins entering the secretory pathway is catalyzed by the protein disulfide isomerase family of endoplasmic reticulum localized oxidoreductases. One such enzyme, ERp57, is thought to catalyze the isomerization of non-native disulfide bonds formed in glycoproteins...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-01, Vol.284 (4), p.2194-2202
Main Authors: Jessop, Catherine E., Tavender, Timothy J., Watkins, Rachel H., Chambers, Joseph E., Bulleid, Neil J.
Format: Article
Language:English
Subjects:
Animals
Calnexin - metabolism
Calreticulin - metabolism
Cell Line
Disulfides - metabolism
Humans
Integrin beta1 - metabolism
Mice
Mice, Knockout
Mutation - genetics
Oxidation-Reduction
Protein Binding
Protein Disulfide-Isomerases - deficiency
Protein Disulfide-Isomerases - genetics
Protein Disulfide-Isomerases - metabolism
Protein Folding
Protein Synthesis, Post-Translational Modification, and Degradation
Substrate Specificity
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Summary:The formation of disulfides within proteins entering the secretory pathway is catalyzed by the protein disulfide isomerase family of endoplasmic reticulum localized oxidoreductases. One such enzyme, ERp57, is thought to catalyze the isomerization of non-native disulfide bonds formed in glycoproteins with unstructured disulfide-rich domains. Here we investigated the mechanism underlying ERp57 specificity toward glycoprotein substrates and the interdependence of ERp57 and the calnexin cycle for their correct folding. Our results clearly show that ERp57 must be physically associated with the calnexin cycle to catalyze isomerization reactions with most of its substrates. In addition, some glycoproteins only require ERp57 for correct disulfide formation if they enter the calnexin cycle. Hence, the specificity of ER oxidoreductases is not only determined by the physical association of enzyme and substrate but also by accessory factors, such as calnexin and calreticulin in the case of ERp57. These conclusions suggest that the calnexin cycle has evolved with a specialized oxidoreductase to facilitate native disulfide formation in complex glycoproteins.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M808054200