title: Retarded protein folding of the human Z-type α₁-antitrypsin variant is suppressed by Cpr2p.
abstract: 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.
authors: Department of Molecular Biology, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea.
authors: Chan-Hun
authors: CH
authors: Jung
authors: Department of Molecular Biology, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea.
authors: Yang-Hee
authors: YH
authors: Kim
authors: Department of Chemistry, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea.
authors: Kyunghee
authors: K
authors: Lee
authors: Department of Molecular Biology, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea. Electronic address: hanaim@sejong.ac.kr.
authors: Hana
authors: H
authors: Im
mesh_terms: D004721:Endoplasmic Reticulum / Q000201:enzymology; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D014644:Genetic Variation; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D009154:Mutation; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D000515:alpha 1-Antitrypsin; C588125:Cpr2 protein, S cerevisiae; D019696:Peptidylprolyl Isomerase
keywords: Folding disease; Peptidyl-prolyl isomerase; Protein folding; Protein interaction; α(1)-Antitrypsin