TY - JOUR
T1 - A pH-Regulated Quality Control Cycle for Surveillance of Secretory Protein Assembly
AU - Vavassori, Stefano
AU - Cortini, Margherita
AU - Masui, Shoji
AU - Sannino, Sara
AU - Anelli, Tiziana
AU - Caserta, Imma R.
AU - Fagioli, Claudio
AU - Mossuto, Maria F.
AU - Fornili, Arianna
AU - vanAnken, Eelco
AU - Degano, Massimo
AU - Inaba, Kenji
AU - Sitia, Roberto
PY - 2013/6/27
Y1 - 2013/6/27
N2 - To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH-regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44's active cysteine, simultaneously unmask the substrate binding site and -RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles.
AB - To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH-regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44's active cysteine, simultaneously unmask the substrate binding site and -RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles.
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U2 - 10.1016/j.molcel.2013.04.016
DO - 10.1016/j.molcel.2013.04.016
M3 - Article
C2 - 23685074
AN - SCOPUS:84880809859
VL - 50
SP - 783
EP - 792
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -