Journal Article

PUBDB-2025-05620

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The mechanism of pathogenic α 1 -antitrypsin aggregation in the human liver

Aldobiyan, I. ; Elliston, E. L. K. ; Heyer-Chauhan, N. ; Arold, S. T. ; Zhao, L. ; Huntington, B. ; Lowen, S. M. ; Orlova, E. V. ; Irving, J. (Corresponding author)Extern*EMBL* ; Lomas, D. A. (Corresponding author)

2025
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2507535122  doi:10.3204/PUBDB-2025-05620

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 structural element (the reactive center loop) as an additional β-strand into the central β-sheet of α1-antitrypsin and displacement of a C-terminal region from one subunit with incorporation into the next. Unlike amyloid aggregation, this well-folded structure partially recapitulates a conformation adopted during normal function of the protein. These perturbations to the constituent α1-antitrypsin subunits of human tissue-derived polymers are consistent with a pronounced stability, their tendency toward long-chain forms, the ability of a subset to undergo canonical secretion, and the action of a class of small molecules that block polymerization in vivo.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
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