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A more recent version of this article appeared on August 1, 2002
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Submitted on February 4, 2002
Revised on May 13, 2002
Accepted on May 17, 2002
1 Departments of Pathology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3498
2 Department of Biochemistry and Molecular Biology, and Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602-7229
* Corresponding author. E-mail address: rsifers{at}bcm.tmc.edu.
Protein folding and quality control in the early secretory pathway functions as a post-translational checkpoint in eukaryote gene expression. Here an aberrant form of the hepatic secretory protein alpha1-antitrypsin (AAT) was stably expressed in the embryonic kidney cell line HEK293 to elucidate the mechanisms by which glycoprotein endoplasmic reticulum associated degradation (GERAD) is administered in cells from higher eukaryotes. Following biosynthesis, genetic variant PI Z underwent alternative phases of secretion and degradation, the latter of which was mediated by the proteasome. Degradation required release from calnexin and asparagine-linked oligosaccharide modification by ER mannosidase I, the latter of which occurred as PI Z was bound to the molecular chaperone grp78/BiP. That a distinct GERAD program operates in HEK293 was supported by the extent of PI Z secretion, apparent lack of polymerization, inability of calnexin to participate in the degradation process, and sequestration of the glycoprotein folding sensor UDP-glucose:glycoprotein glucosyltransferase (UGT) in the Golgi complex. Since UGT sustains calnexin binding, its altered distribution is consistent with a GERAD program that hinders the reentry of substrates into the calnexin cycle, allowing grp78/BiP to partner with a lectin, other than calnexin, in the recognition of a two-component GERAD signal to facilitate substrate recruitment. How the processing of a mutant protein, rather than the mutation itself, can contribute to disease pathogenesis, is discussed.
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