A pH-Regulated Quality Control Cycle for Surveillance of Secretory Protein Assembly

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 mec...

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Bibliographic Details
Published in:	Molecular cell Vol. 50; no. 6; pp. 783 - 792
Main Authors:	Vavassori, Stefano, Cortini, Margherita, Masui, Shoji, Sannino, Sara, Anelli, Tiziana, Caserta, Imma R., Fagioli, Claudio, Mossuto, Maria F., Fornili, Arianna, van Anken, Eelco, Degano, Massimo, Inaba, Kenji, Sitia, Roberto
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 27-06-2013 Cell Press
Subjects:	adiponectin Amino Acid Motifs Amino Acid Substitution binding sites calnexin calreticulin Catalytic Domain Cell Cycle cysteine endoplasmic reticulum Endoplasmic Reticulum - metabolism Golgi Apparatus - metabolism HeLa Cells Humans Hydrogen-Ion Concentration immunoglobulin M Membrane Glycoproteins - metabolism Membrane Proteins - chemistry Membrane Proteins - genetics Membrane Proteins - metabolism Models, Molecular Molecular Chaperones - chemistry Molecular Chaperones - genetics Molecular Chaperones - metabolism monitoring Mutagenesis, Site-Directed Oxidoreductases - metabolism Protein Multimerization protein subunits Protein Transport proteome quality control quality controls receptors secretion Secretory Pathway stress response
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Summary:	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. [Display omitted] •ERp44 governs a pH-regulated assembly control cycle in the early secretory pathway•Accessibility of ERp44’s active site and –RDEL ER retrieval motif is pH dependent•Unmasking of ERp44’s active site likely involves protonation of cysteine 29•ERp44 captures client proteins at cisGolgi-equivalent pH for retrieval to the ER
Bibliography:	http://dx.doi.org/10.1016/j.molcel.2013.04.016 Present address: Department of Life Science, Università of Modena and Reggio Emilia, 42121 Modena, Italy These authors contributed equally to this work Present address: Département de Biochimie, Université de Lausanne, Epalinges CH-1015, Switzerland Present address: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, Sendai 980-8577, Japan Present address: Randall Division of Cell and Molecular Biophysics, King’s College, New Hunt’s House, London SE1 1UL, UK
ISSN:	1097-2765 1097-4164
DOI:	10.1016/j.molcel.2013.04.016