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
N1 - Funding Information:
We thank members of our labs for helpful suggestions, Jose Garcia-Manteiga and Alessandro Ambrosi for advice on statistical analyses, and the ALEMBIC Facility and Elena Pasqualetto for technical assistance. This work was supported by grants from Telethon (GGP11077), Associazione Italiana Ricerca Cancro (AIRC, IG10721, and 5 × 1000 SP9965), Fondazione Cariplo (NOBEL), Ministero della Salute, Regione Lombardia (ASTIL) to M.D. and R.S., and the Funding Program for Next Generation World-Leading Researchers from MEXT (to K.I.). S.M. is a research fellow of Japan Society for the Promotion of Science (JSPS). E.v.A. is supported through an Armenise Harvard Career Development Award and AIRC (MFAG13584 AIRC). M.F.M. is supported by a FEBS Fellowship. S.V., M.C., M.D., K.I., and R.S. designed the study and planned most of the experiments. S.V., S.M., and C.F. performed the in vitro experiments. M.C., S.S., T.A., and I.R.C. performed the in vivo experiments. A.F. and M.D. carried out the structural analysis and in silico studies. E.v.A., M.F.M., M.D., K.I., and R.S. helped in interpreting the results and with M.C. and S.V. played a major role in writing the manuscript.
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
SN - 1097-2765
VL - 50
SP - 783
EP - 792
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -