Folding and stability of the Z and S-iiyama genetic variants of human alpha(1)-antitrypsinopen access
- Authors
- Kang, Hyun Ah; Lee, Kee Nyung; Yu, Myeong-Hee
- Issue Date
- Jan-1997
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Citation
- JOURNAL OF BIOLOGICAL CHEMISTRY, v.272, no.1, pp 510 - 516
- Pages
- 7
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Volume
- 272
- Number
- 1
- Start Page
- 510
- End Page
- 516
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/57003
- DOI
- 10.1074/jbc.272.1.510
- ISSN
- 0021-9258
1083-351X
- Abstract
- Z (Glu(342) --> Lys) and S-iiyama (Ser(53) --> Phe) genetic variations of human alpha(1)-antitrypsin (alpha(1)-AT) cause a secretion blockage in the hepatocytes, leading to alpha(1)-AT deficiency in the plasma, Using in vitro folding analysis, we have shown previously that these mutations interfere with the proper folding of polypeptides. To understand the fundamental cause for the secretion defect of the Z and S-iiyama variants of alpha(1)-AT, we investigated in vivo folding and stability of these variant alpha(1)-AT using the secretion system of yeast Saccharomyces cerevisiae, Various thermostable mutations suppressing the folding block of the Z variant in vitro corrected the secretion defect as well as the intracellular degradation in the yeast secretion system, Significantly, the extent of suppression in the secretion defect of Z protein was proportional to the extent of suppression in the folding defect, assuring that the in vivo defect associated with the Z variant is primarily derived from the folding block. In contrast, the folding and secretion efficiency of S-iiyama was not much improved by the same mutations, In addition, none of the rarely secreted S-iiyama alpha(1)-AT carrying the stabilizing mutations for the wild type and Z variant were active, It appears that the major defect in S-iiyama variant is the loss of stability in contrast to the kinetic block of folding in the Z variant.
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