Faull, SV;
Elliston, ELK;
Gooptu, B;
Jagger, AM;
Aldobiyan, I;
Redzej, A;
Badaoui, M;
... Lomas, DA; + view all
(2020)
The structural basis for Z α₁-antitrypsin polymerization in the liver.
Science Advances
, 6
(43)
, Article eabc1370. 10.1126/sciadv.abc1370.
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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.
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