The structural basis for Z ?1-antitrypsin polymerization in the liver.

ABSTRACT: The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. ?1-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of ?1-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 ?1-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 ?1-antitrypsin.

SUBMITTER: Faull SV 

PROVIDER: S-EPMC7577719 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature