NDLI: Folding and Stability of the Z and Siiyama Genetic Variants of Human α1-Antitrypsin

Content Provider	Journal of Biological Chemistry (JBC)
Author	Kang, Hyun Ah Lee, Kee Nyung Yu, Myeong-Hee
Abstract	Z (Glu342 → Lys) and Siiyama (Ser53 → Phe) genetic variations of human α1-antitrypsin (α1-AT) cause a secretion blockage in the hepatocytes, leading to α1-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 Siiyama variants of α1-AT, we investigated in vivo folding and stability of these variant α1-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 Siiyama was not much improved by the same mutations. In addition, none of the rarely secreted Siiyama α1-AT carrying the stabilizing mutations for the wild type and Z variant were active. It appears that the major defect in Siiyama variant is the loss of stability in contrast to the kinetic block of folding in the Z variant.
Related Links	http://www.jbc.org/content/272/1/510.abstract
Ending Page	516
Starting Page	510
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	1
Volume Number	272
DOI	10.1074/jbc.272.1.510
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1997-01-03
Access Restriction	Open
Subject Keyword	Protein Chemistry and Structure
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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