1. Modulation of Cellular Disulfide-Bond Formation and the ER Redox Environment by Feedback Regulation of Ero1
- Author
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Deborah Fass, Nimrod Heldman, Carolyn S. Sevier, Einav Gross, Chris A. Kaiser, and Hongjing Qu
- Subjects
Saccharomyces cerevisiae Proteins ,PROTEINS ,Mutant ,Saccharomyces cerevisiae ,Endoplasmic Reticulum ,Redox ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,ER oxidoreductin ,Oxidoreductases Acting on Sulfur Group Donors ,Disulfides ,Protein disulfide-isomerase ,Secretory pathway ,Glycoproteins ,030304 developmental biology ,Feedback, Physiological ,0303 health sciences ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,Endoplasmic reticulum ,Substrate (chemistry) ,3. Good health ,Biochemistry ,biology.protein ,Biophysics ,Cystine ,CELLBIO ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Cysteine - Abstract
SummaryIntroduction of disulfide bonds into proteins entering the secretory pathway is catalyzed by Ero1p, which generates disulfide bonds de novo, and Pdi1p, which transfers disulfides to substrate proteins. A sufficiently oxidizing environment must be maintained in the endoplasmic reticulum (ER) to allow for disulfide formation, but a pool of reduced thiols is needed for isomerization of incorrectly paired disulfides. We have found that hyperoxidation of the ER is prevented by attenuation of Ero1p activity through noncatalytic cysteine pairs. Deregulated Ero1p mutants lacking certain cysteines show increased enzyme activity, a decreased lag phase in kinetic assays, and growth defects in vivo. We hypothesize that noncatalytic cysteine pairs in Ero1p sense the level of potential substrates in the ER and correspondingly modulate Ero1p activity as part of a homeostatic regulatory system governing the thiol-disulfide balance in the ER.
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