The mechanism of pathogenic α₁-antitrypsin aggregation in the human liver.

ABSTRACT: Originating 2 to 3 millennia ago in a Scandinavian population, the SERPINA1 Z allele (Glu342Lys) is present in up to 2.5% of populations of Northern European descent and accounts for 95% of severe α₁-antitrypsin deficiency. The α₁-antitrypsin Z variant self-assembles into polymer chains that deposit within hepatocytes, predisposing to liver disease. Here, the 4.0Å subunit structure of polymers isolated directly from human liver tissue has been determined using cryoelectron microscopy. Challenges of flexibility, small subunit size, heterogeneous length, and preferred orientations were mitigated using antibody Fab domains and sample preparation strategies. This structure demonstrates that the formation of polymers in vivo involves self-incorporation of an exposed struct

SUBMITTER: Aldobiyan I 

PROVIDER: S-EPMC12646233 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature