The structural basis for Z alpha 1 -antitrypsin polymerization in the liver.
Faull, S.V., Elliston, E.L.K., Gooptu, B., Jagger, A.M., Aldobiyan, I., Redzej, A., Badaoui, M., Heyer-Chauhan, N., Rashid, S.T., Reynolds, G.M., Adams, D.H., Miranda, E., Orlova, E.V., Irving, J.A., Lomas, D.A.(2020) Sci Adv 6
- PubMed: 33087346 
- DOI: https://doi.org/10.1126/sciadv.abc1370
- Primary Citation of Related Structures:  
6QU9 - PubMed Abstract: 
The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α 1 -Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α 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 α 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 α 1 -antitrypsin.
Organizational Affiliation: 
UCL Respiratory, University College London, 5 University Street, London WC1E 6JF, UK.