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Title 

Metastability in the inhibitory mechanism of human α₁-antitrypsin

Authors 

Hana ImEun Joo SeoMyeong Hee Yu

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

1999

Citation 

Journal of Biological Chemistry, vol. 274, no. 16, pp. 11072-11077

Keywords 

alpha 1 antitrypsinalpha 1-Antitrypsinhumans

Abstract 

Metastability of the native form of proteins has been recognized as a mechanism of biological regulation. The energy-loaded structure of the fusion protein of influenza virus and the strained native structure of serpins (serine protease inhibitors) are typical examples. To understand the structural basis and functional role of the native metastability of inhibitory serpins, we characterized stabilizing mutations of α1- antitrypsin in a region presumably involved in complex formation with a target protease. We found various unfavorable interactions such as overpacking of side chains, polar-nonpolar interactions, and cavities as the structural basis of the native metastability. For several stabilizing mutations, there was a concomitant decrease in the inhibitory activity. Remarkably, some substitutions at Lys-335 increased the stability over 6 kcal mol-1 with simultaneous loss of activity over 30% toward porcine pancreatic elastase. Considering the location and energetic cost of Lys-335, we propose that this lysine plays a pivotal role in conformational switch during complex formation. Our current results are quite contradictory to those of previously reported hydrophobic core mutations, which increased the stability up to 9 kcal mol-1 without any significant loss of activity. It appears that the local strain of inhibitory serpins is critical for the inhibitory activity.

ISSN 

0021-9258

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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