Protein Science
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Published online before print February 6, 2004
Protein Science, DOI: 10.1110/ps.03356604
 Copyright © 2004 The Protein Society
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ps.03356604v1
13/3/694    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jung, C.-H.
Right arrow Articles by Im, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jung, C.-H.
Right arrow Articles by Im, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Med. Genet.Home page
P K Lovelock, S Healey, W Au, E Y M Sum, A Tesoriero, E M Wong, S Hinson, R Brinkworth, A Bekessy, O Diez, et al.
Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants
J. Med. Genet., January 1, 2006; 43(1): 74 - 83.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Copyright © 2004 by The Protein Society.