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Characterization of a human alpha1-antitrypsin variant that is as stable as ovalbumin
- Source :
- The Journal of biological chemistry. 273(5)
- Publication Year :
- 1998
-
Abstract
- The metastability of inhibitory serpins (serine proteinase inhibitors) is thought to play a key role in the facile conformational switch and the insertion of the reactive center loop into the central beta-sheet, A-sheet, during the formation of a stable complex between a serpin and its target proteinase. We have examined the folding and inhibitory activity of a very stable variant of human alpha1-antitrypsin, a prototype inhibitory serpin. A combination of seven stabilizing single amino acid substitutions of alpha1-antitrypsin, designated Multi-7, increased the midpoint of the unfolding transition to almost that of ovalbumin, a non-inhibitory but more stable serpin. Compared with the wild-type alpha1-antitrypsin, Multi-7 retarded the opening of A-sheet significantly, as revealed by the retarded unfolding and latency conversion of the native state. Surprisingly, Multi-7 alpha1-antitrypsin could form a stable complex with a target elastase with the same kinetic parameters and the stoichiometry of inhibition as the wild type, indicating that enhanced A-sheet closure conferred by Multi-7 does not affect the complex formation. It may be that the stability increase of Multi-7 alpha1-antitrypsin is not sufficient to influence the rate of loop insertion during the complex formation.
- Subjects :
- Models, Molecular
Protein Denaturation
Protein Folding
biology
Pancreatic Elastase
Stereochemistry
Chemistry
Ovalbumin
Protein Conformation
Elastase
Wild type
Cell Biology
Serpin
Biochemistry
Models, Chemical
alpha 1-Antitrypsin
Mutation
Native state
biology.protein
Humans
Serine Proteinase Inhibitors
Molecular Biology
Pancreatic elastase
Reactive center
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 273
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....1f488f8a3547dfeed92cd12a5355d12c