title: A pH-regulated quality control cycle for surveillance of secretory protein assembly.
abstract: 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.
authors.affiliation: Division of Genetics, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Vavassori
authors.forename: Margherita
authors.initials: M
authors.lastname: Cortini
authors.forename: Shoji
authors.initials: S
authors.lastname: Masui
authors.forename: Sara
authors.initials: S
authors.lastname: Sannino
authors.forename: Tiziana
authors.initials: T
authors.lastname: Anelli
authors.forename: Imma R
authors.initials: IR
authors.lastname: Caserta
authors.forename: Claudio
authors.initials: C
authors.lastname: Fagioli
authors.forename: Maria F
authors.initials: MF
authors.lastname: Mossuto
authors.forename: Arianna
authors.initials: A
authors.lastname: Fornili
authors.forename: Eelco
authors.initials: E
authors.lastname: van Anken
authors.forename: Massimo
authors.initials: M
authors.lastname: Degano
authors.forename: Kenji
authors.initials: K
authors.lastname: Inaba
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D002453:Cell Cycle; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010088:Oxidoreductases / Q000378:metabolism; D055503:Protein Multimerization; D021381:Protein Transport; D055571:Secretory Pathway
chemical_list: C451899:ERP44 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C405327:ERO1A protein, human; D010088:Oxidoreductases