title: Consequences of ERp57 deletion on oxidative folding of obligate and facultative clients of the calnexin cycle.
abstract: Members of the protein-disulfide isomerase superfamily catalyze the formation of intra- and intermolecular disulfide bonds, a rate-limiting step of protein folding in the endoplasmic reticulum (ER). Here we compared maturation of one obligate and two facultative calnexin substrates in cells with and without ERp57, the calnexin-associated, glycoprotein-specific oxidoreductase. ERp57 deletion did not prevent the formation of disulfide bonds during co-translational translocation of nascent glycopolypeptides in the ER. It affected, however, the post-translational phases of oxidative influenza virus hemagglutinin (HA) folding, resulting in significant loss of folding efficiency for this obligate calnexin substrate. Without ERp57, HA also showed reduced capacity to recover from an artificially induced aberrant conformation, thus revealing a crucial role of ERp57 during post-translational reshuffling to the native set of HA disulfides. ERp57 deletion did not affect maturation of the model facultative calnexin substrates E1 and p62 (and of most cellular proteins, as shown by lack of induction of ER stress). ERp72 was identified as one of the ER-resident oxidoreductases associating with the orphan ERp57 substrates to maintain their folding competence.
authors.affiliation: Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Soldà
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Maurizio
authors.initials: M
authors.lastname: Molinari
mesh_terms: D000818:Animals; D037281:Calnexin / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002461:Cell Line, Transformed; D003553:Cystine / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics*; D006388:Hemagglutinins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases / Q000172:deficiency* / Q000235:genetics*; D017510:Protein Folding; D017384:Sequence Deletion
chemical_list: D006360:Heat-Shock Proteins; D006388:Hemagglutinins; D008562:Membrane Glycoproteins; C062477:endoplasmic reticulum glycoprotein p72; D037281:Calnexin; D003553:Cystine; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases