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PEDS Advance Access originally published online on May 4, 2004
Protein Engineering Design and Selection 2004 17(4):325-331; doi:10.1093/protein/gzh036
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Protein Engineering, Design & Selection vol. 17 no. 4 © Oxford University Press 2004; all rights reserved

Engineering thermostability in serine protease inhibitors

Hana Im1,2, Myung-Jeom Ryu2 and Myeong-Hee Yu2,3

1Department of Molecular Biology, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747 and 2Functional Proteomics Center, Korea Institute of Science and Technology, 39–1 Hawolgok-dong, Sungbuk-gu, Seoul 136-791, Korea

3 To whom correspondence should be addressed. E-mail: mhyu{at}kist.re.kr

Unlike most globular proteins, the native form of serine protease inhibitors (serpins) is strained. Previous studies of human {alpha}1-antitrypsin, a prototype plasma serpin, revealed that various unfavorable interactions, such as overpacking of side chains, buried polar groups and cavities, are the structural basis of the strain. The local strain could be relieved by various stabilizing single amino acid substitutions, which appeared to remove these unfavorable interactions. To improve the stability of other clinically important serpin members, here we examined whether the rules found in {alpha}1-antitrypsin studies are applicable to other serpins. Amino acid substitutions were introduced at various positions in human {alpha}1-antichymotrypsin and human antithrombin III that were equivalent to the sites of stabilizing substitutions of {alpha}1-antitrypsin. Two-thirds of the substitutions increased thermostability in all serpins tested. Mutational analysis and structural examination suggest that serpins are suboptimally folded using common structural strategies at many sites, even though some structural details can vary in individual members. The results suggest that schemes discovered with {alpha}1-antitrypsin, an easily manipulative serpin, are a useful basis for engineering conformational characteristics of other clinically important serpins.

Received December 31, 2003; revised April 13, 2004; accepted April 13, 2004.

Edited by Andreas Matouschek


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