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Published online before print February 6, 2004, 10.1110/ps.03356604
Protein Science (2004), 13:694-702. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Retarded protein folding of deficient human {alpha}1-antitrypsin D256V and L41P variants

Chan-Hun Jung, Yu-Ran Na and Hana Im

Department of Molecular Biology, Sejong University, Kwangjin-gu, Seoul 143-747, Korea

(RECEIVED August 7, 2003; FINAL REVISION November 28, 2003; ACCEPTED November 29, 2003)



Abstract

{alpha}1-Antitrypsin is the most abundant protease inhibitor in plasma and is the archetype of the serine protease inhibitor superfamily. Genetic variants of human {alpha}1-antitrypsin are associated with early-onset emphysema and liver cirrhosis. However, the detailed molecular mechanism for the pathogenicity of most variant {alpha}1-antitrypsin molecules is not known. Here we examined the structural basis of a dozen deficient {alpha}1-antitrypsin variants. Unlike most {alpha}1-antitrypsin variants, which were unstable, D256V and L41P variants exhibited extremely retarded protein folding as compared with the wild-type molecule. Once folded, however, the stability and inhibitory activity of these variant proteins were comparable to those of the wild-type molecule. Retarded protein folding may promote protein aggregation by allowing the accumulation of aggregation-prone folding intermediates. Repeated observations of retarded protein folding indicate that it is an important mechanism causing {alpha}1-antitrypsin deficiency by variant molecules, which have to fold into the metastable native form to be functional.

Keywords: {alpha}1-antitrypsin; conformational disease; folding; metastability; serpin

Reprint requests to: Hana Im, Department of Molecular Biology, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Korea; e-mail: hanaim{at}sejong.ac.kr; fax: 82-2-3408-3661.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03356604.


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