Modulation of Cellular Disulfide-Bond Formation and the ER Redox Environment by Feedback Regulation of Ero1

Carolyn S. Sevier, Hongjing Qu, Nimrod Heldman, Einav Gross, Deborah Fass, Chris A. Kaiser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

204 Scopus citations


Introduction 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.

Original languageAmerican English
Pages (from-to)333-344
Number of pages12
Issue number2
StatePublished - 20 Apr 2007
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Colin Thorpe for helpful suggestions. Tevie Mehlman and Alla Shainskaya from the Biological Mass Spectrometry Unit at the Weizmann Institute provided LC-MS/MS data. This work was supported by grants from the National Institutes of Health (GM46941) to C.A.K. and from the U.S.-Israel Binational Science Foundation (to D.F. and C.A.K.). D.F. is incumbent of the Lilian and George Lyttle Career Development Chair.




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