The structural basis for Z 1-antitrypsin polymerization.pdf (5.31 MB)
The structural basis for Z α1-antitrypsin polymerisation in the liver
journal contributionposted on 2020-11-06, 14:32 authored by Sarah V. Faull, Emma L. K. Elliston, Bibek Gooptu, Alistair M. Jagger, Ibrahim AldobiyanIbrahim 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
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.
CitationScience Advances, 21 Oct 2020:, Vol. 6, no. 43, eabc1370, DOI: 10.1126/sciadv.abc1370
Author affiliationLeicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology
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