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Altered native stability is the dominant basis for susceptibility of α1-antitrypsin mutants to polymerisation.

Irving, JA; Haq, I; Dickens, JA; Faull, SV; Lomas, DA; (2014) Altered native stability is the dominant basis for susceptibility of α1-antitrypsin mutants to polymerisation. Biochem J , 460 (1) pp. 103-115. 10.1042/BJ20131650. Green open access

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Abstract

Serpins are protease inhibitors whose most stable state is achieved upon transition of a central five-stranded β-sheet to a six-stranded form. Mutations, low pH, denaturants, and elevated temperatures promote this transition, which can result in a growing polymer chain of inactive molecules. Different types of polymer are possible, but experimentally, only heat has been shown to generate polymers in vitro consistent with ex vivo pathological specimens. Many mutations that alter the rate of heat-induced polymerisation have been described, but interpretation is problematic, because discrimination is lacking between the effect of global changes in native stability and specific effects on structural mechanism. We show that the temperature midpoint (Tm) of thermal denaturation reflects the transition of α1-antitrypsin to the polymerisation intermediate, and determine the relationship with fixed-temperature polymerisation half-times (t0.5) in the presence of stabilising additives (TMAO, sucrose and sodium sulphate), point mutations and disulphide bonds. Combined with a retrospective analysis of 31 mutants characterised in the literature, our data show that global changes to native state stability are the predominant basis for the effects of mutations and osmolytes on heat-induced polymerisation, summarised by the equation: ln(t0.5,mutant/t0.5,wild-type)=0.34×ΔTm. It is deviations from this relationship that hold key information about the polymerisation process.

Type: Article
Title: Altered native stability is the dominant basis for susceptibility of α1-antitrypsin mutants to polymerisation.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/BJ20131650
Publisher version: http://dx.doi.org/10.1042/BJ20131650
Additional information: © 2014 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Licence (CC-BY) (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: cirrhosis, denaturation, disulfide, polymerization, serpin, stability.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/1420660
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