Retarded protein folding of the human Z-type α₁-antitrypsin variant is suppressed by Cpr2p.

The human Z-type α1-antitrypsin variant has a strong tendency to accumulate folding intermediates due to extremely slow protein folding within the endoplasmic reticulum (ER) of hepatocytes. Human α1-antitrypsin has 17 peptidyl-prolyl bonds per molecule; thus, the effect of peptidyl-prolyl isomerases on Z-type α1-antitrypsin protein folding was analyzed in this study. ...
The protein level of Cpr2p, a yeast ER peptidyl-prolyl isomerase, increased more than two-fold in Z-type α1-antitrypsin-expressing yeast cells compared to that in wild-type α1-antitrypsin-expressing cells. When CPR2 was deleted from the yeast genome, the cytotoxicity of Z-type α1-antitrypsin increased significantly. The interaction between Z-type α1-antitrypsin and Cpr2p was confirmed by co-immunoprecipitation. In vitro folding assays showed that Cpr2p facilitated Z-type α1-antitrypsin folding into the native state. Furthermore, Cpr2p overexpression significantly increased the extracellular secretion of Z-type α1-antitrypsin. Our results indicate that ER peptidyl-prolyl isomerases may rescue Z-type α1-antitrypsin molecules from retarded folding and eventually relieve clinical symptoms caused by this pathological α1-antitrypsin.
Mesh Terms:
Endoplasmic Reticulum, Gene Expression Regulation, Genetic Complementation Test, Genetic Variation, Humans, Immunoblotting, Immunoprecipitation, Mutation, Peptidylprolyl Isomerase, Protein Binding, Protein Folding, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, alpha 1-Antitrypsin
Biochem. Biophys. Res. Commun.
Date: Feb. 28, 2014
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