DOI: 10.1083/jcb.138.6.1229. Active Site Mutations in Yeast Protein Disulfide Isomerase Cause Dithiothreitol Sensitivity and a Reduced Rate of Protein Folding in the Endoplasmic Reticulum

Active Site Mutations in Yeast Protein Disulfide Isomerase Cause Dithiothreitol Sensitivity and a Reduced Rate of Protein Folding in the Endoplasmic Reticulum

10.1083/jcb.138.6.1229

Crossref journal-article

Rockefeller University Press

The Journal of Cell Biology (291)

Abstract

Aspects of protein disulfide isomerase (PDI) function have been studied in yeast in vivo. PDI contains two thioredoxin-like domains, a and a′, each of which contains an active-site CXXC motif. The relative importance of the two domains was analyzed by rendering each one inactive by mutation to SGAS. Such mutations had no significant effect on growth. The domains however, were not equivalent since the rate of folding of carboxypeptidase Y (CPY) in vivo was reduced by inactivation of the a domain but not the a′ domain. To investigate the relevance of PDI redox potential, the G and H positions of each CGHC active site were randomly mutagenized. The resulting mutant PDIs were ranked by their growth phenotype on medium containing increasing concentrations of DTT. The rate of CPY folding in the mutants showed the same ranking as the DTT sensitivity, suggesting that the oxidative power of PDI is an important factor in folding in vivo. Mutants with a PDI that cannot perform oxidation reactions on its own (CGHS) had a strongly reduced growth rate. The growth rates, however, did not correlate with CPY folding, suggesting that the protein(s) required for optimal growth are dependent on PDI for oxidation. pdi1-deleted strains overexpressing the yeast PDI homologue EUG1 are viable. Exchanging the wild-type Eug1p C(L/I)HS active site sequences for C(L/I)HC increased the growth rate significantly, however, further highlighting the importance of the oxidizing function for optimal growth.

Bibliography

Holst, B., Tachibana, C., & Winther, J. R. (1997). Active Site Mutations in Yeast Protein Disulfide Isomerase Cause Dithiothreitol Sensitivity and a Reduced Rate of Protein Folding in the Endoplasmic Reticulum. The Journal of Cell Biology, 138(6), 1229â1238.

Authors 3

Bjørn Holst (first)
Christine Tachibana (additional)
Jakob R. Winther (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:47 p.m.)
Deposited	2 years, 1 month ago (July 22, 2023, 3:14 a.m.)
Indexed	2 months, 1 week ago (June 20, 2025, 9:24 a.m.)
Issued	27 years, 11 months ago (Sept. 22, 1997)
Published	27 years, 11 months ago (Sept. 22, 1997)
Published Online	27 years, 11 months ago (Sept. 22, 1997)
Published Print	27 years, 11 months ago (Sept. 22, 1997)

Funders 0

None

BibTeX

@article{Holst_1997, title={Active Site Mutations in Yeast Protein Disulfide Isomerase Cause Dithiothreitol Sensitivity and a Reduced Rate of Protein Folding in the Endoplasmic Reticulum}, volume={138}, ISSN={1540-8140}, url={http://dx.doi.org/10.1083/jcb.138.6.1229}, DOI={10.1083/jcb.138.6.1229}, number={6}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Holst, Bjørn and Tachibana, Christine and Winther, Jakob R.}, year={1997}, month=sep, pages={1229–1238} }

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