The structural basis for Z α1-antitrypsin polymerization in the liver

Sarah V Faull; Emma L K Elliston; Bibek Gooptu; Alistair M Jagger; Ibrahim Aldobiyan; Adam Redzej; Magd Badaoui; Nina Heyer-Chauhan; S Tamir Rashid; Gary M Reynolds; David H Adams; Elena Miranda; Elena V Orlova; James A Irving; David A Lomas

doi:10.1126/sciadv.abc1370

The structural basis for Z α₁-antitrypsin polymerization in the liver

Sci Adv. 2020 Oct 21;6(43):eabc1370. doi: 10.1126/sciadv.abc1370. Print 2020 Oct.

Authors

Sarah V Faull¹, Emma L K Elliston^{1

2}, Bibek Gooptu^{3

4

5}, Alistair M Jagger^{1

2}, Ibrahim Aldobiyan^{1

2}, Adam Redzej⁵, Magd Badaoui¹, Nina Heyer-Chauhan^{1

2}, S Tamir Rashid⁶, Gary M Reynolds⁷, David H Adams⁷, Elena Miranda⁸, Elena V Orlova⁵, James A Irving^{9

2}, David A Lomas^{9

2}

Affiliations

¹ UCL Respiratory, University College London, 5 University Street, London WC1E 6JF, UK.
² Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BN, UK.
³ Leicester Institute of Structural and Chemical Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7HB, UK.
⁴ National Institute for Health Research (NIHR) Leicester BRC-Respiratory, Leicester, UK.
⁵ Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, University of London, London WC1E 7HX, UK.
⁶ Centre for Stem Cells and Regenerative Medicine and Institute for Liver Studies, King's College London, London WC2R 2LS, UK.
⁷ Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
⁸ Department of Biology and Biotechnologies "Charles Darwin" and Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
⁹ UCL Respiratory, University College London, 5 University Street, London WC1E 6JF, UK. [email protected] [email protected].

Abstract

The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α₁-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α₁-antitrypsin as "polymer" chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α₁-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α₁-antitrypsin.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Publication types

Research Support, Non-U.S. Gov't

Abstract

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