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

DOI: 10.1126/sciadv.abc1370 DOI Help

Authors: Sarah V. Faull (University College London) , Emma L. K. Elliston (University College London) , Bibek Gooptu (University of Leicester; National Institute for Health Research (NIHR) Leicester BRC-Respiratory; Birkbeck College, University of London) , Alistair M. Jagger (University College London) , Ibrahim Aldobiyan (University College London) , Adam Redzej (Birkbeck, University of London) , Magd Badaoui (University College London) , Nina Heyer-Chauhan (University College London) , S. Tamir Rashid (King’s College London) , Gary M. Reynolds (University of Birmingham) , David H. Adams (University of Birmingham) , Elena Miranda (gies “Charles Darwin” and Pasteur Institute—Cenci Bolognetti Foundation) , Elena V. Orlova (Birkbeck, University of London) , James A. Irving (University College London) , David A. Lomas (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 17201

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Other Facilities: ID30B at ESRF

Added On: 28/10/2020 09:56


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)