Haq, I;
Irving, JA;
Saleh, AD;
Dron, L;
Regan-Mochrie, GL;
Motamedi-Shad, N;
Hurst, JR;
... Lomas, DA; + view all
(2016)
Deficiency Mutations of α1-antitrypsin Differentially Affect Folding, Function and Polymerization.
American Journal of Respiratory Cell and Molecular Biology
, 54
(1)
pp. 71-80.
10.1165/rcmb.2015-0154OC.
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Abstract
Misfolding, polymerisation and defective secretion of functional α1-antitrypsin underlies the predisposition to severe liver and lung disease in α1-antitrypsin deficiency. We have identified a novel (Ala336Pro, Baghdad) deficiency variant and characterised it relative to the wild-type (M) and Glu342Lys (Z) alleles. The index case is a homozygous individual of consanguineous parentage, with levels of circulating α1-antitrypsin in the moderate deficiency range, but a biochemical phenotype that could not be classified by standard methods. The majority of the protein was present as functionally inactive polymer, and the remaining monomer was 37% active relative to the wild-type protein. These factors combined indicate a 85-95% functional deficiency, similar to that seen with ZZ homozygotes. Biochemical, biophysical and computational studies further defined the molecular basis of this deficiency. These demonstrated that native Ala336Pro α1-antitrypsin could populate the polymerogenic intermediate - and therefore polymerise - more readily than either wild-type α1-antitrypsin or the Z variant. In contrast, folding was far less impaired in Ala336Pro α1-antitrypsin than in the Z variant. The data are consistent with a disparate contribution by the 'breach' region and 'shutter' region of strand 5A to folding and to polymerisation mechanisms. Moreover, the findings demonstrate that in these variants, folding efficiency does not correlate directly with the tendency to polymerise in vitro or in vivo. They therefore differentiate generalised misfolding from polymerisation tendencies in missense variants of α1-antitrypsin. Clinically they further support the need to quantify loss-of-function in α1-antitrypsin deficiency to individualise patient care.
| Type: | Article |
|---|---|
| Title: | Deficiency Mutations of α1-antitrypsin Differentially Affect Folding, Function and Polymerization |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1165/rcmb.2015-0154OC |
| Publisher version: | http://dx.doi.org/10.1165/rcmb.2015-0154OC |
| Language: | English |
| Additional information: | Copyright © 2015 by the American Thoracic Society. Originally Published in: [Haq, I; Irving, JA; Saleh, AD; Dron, L; Regan-Mochrie, GL; Motamedi-Shad, N; Hurst, JR; (2016) Deficiency Mutations of α1-antitrypsin Differentially Affect Folding, Function and Polymerization. American Journal of Respiratory Cell and Molecular Biology , 54 (1) pp. 71-80. 10.1165/rcmb.2015-0154OC]. The final publication is available at http://dx.doi.org/10.1165/rcmb.2015-0154OC |
| Keywords: | Mutation, Protease inhibition, Protein stability, Serpinopathy, α1-Antitrypsin deficiency |
| 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/1469559 |
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