title: Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control.
abstract: Misfolded proteins retained in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation pathway. The mechanisms used to sort them from correctly folded proteins remain unclear. Analysis of substrates with defined folded and misfolded domains has revealed a system of sequential checkpoints that recognize topologically distinct domains of polypeptides. The first checkpoint examines the cytoplasmic domains of membrane proteins. If a lesion is detected, it is retained statically in the ER and rapidly degraded without regard to the state of its other domains. Proteins passing this test face a second checkpoint that monitors domains localized in the ER lumen. Proteins detected by this pathway are sorted from folded proteins and degraded by a quality control mechanism that requires ER-to-Golgi transport. Although the first checkpoint is obligatorily directed at membrane proteins, the second monitors both soluble and membrane proteins. Our data support a model whereby "properly folded" proteins are defined biologically as survivors that endure a series of distinct checkpoints.
authors.affiliation: Department of Biochemistry and Molecular Biology, 408 South Frear Laboratory, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Vashist
authors.forename: Davis T W
authors.initials: DT
authors.lastname: Ng
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D006023:Glycoproteins; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D007425:Intracellular Membranes / Q000378:metabolism; D008361:Mannosidases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D006023:Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D010455:Peptides; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; C434527:MNL1 protein, S cerevisiae; D008361:Mannosidases