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    Deficiency mutations of α1-antitrypsin differentially affect folding, function and polymerization

    Haq, I. and Irving, J. and Saleh, A.D. and Dron, L. and Regan-Mochrie, G.L. and Motamedi-Shad, N. and Hurst, J.R. and Gooptu, Bibek and Lomas, D.A. (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. ISSN 1044-1549.

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    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.


    Item Type: Article
    Additional Information: *Bibek Gooptu credited as joint senior/corresponding author*
    Keyword(s) / Subject(s): Serpinopathy, Protein stability, Protease inhibition, α1-Antitrypsin deficiency, Mutation
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 22 Jun 2015 09:22
    Last Modified: 02 Aug 2023 17:17


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