9HUD

Alpha-1-antitrypsin in the cleaved conformation in complex with a conformationally nonselective Fab fragment

Summary for 9HUD

• Entry DOI: 10.2210/pdb9hud/pdb
• Descriptor: Alpha-1-antitrypsin, LYSINE, Short peptide from AAT, ... (11 entities in total)
• Functional Keywords: complex, cleaved alpha-1-antitrypsin, alpha-1-antitrypsin, antitrypsin, fab, fab fragment, fragment antigen-binding region, antibody antigen complex, 9c5, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 186540.55

Authors

Irving, J.A.,Aldobiyan, I.F. (deposition date: 2024-12-22, release date: 2025-11-26)

Primary citation

Aldobiyan, I.,Elliston, E.L.K.,Heyer-Chauhan, N.,Arold, S.T.,Zhao, L.,Huntington, B.,Lowen, S.M.,Orlova, E.V.,Irving, J.A.,Lomas, D.A.
The mechanism of pathogenic alpha 1 -antitrypsin aggregation in the human liver.
Proc.Natl.Acad.Sci.USA, 122:e2507535122-e2507535122, 2025

PubMed 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 α-antitrypsin deficiency. The α-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 α-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 α-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.

PubMed: 41231946
DOI: 10.1073/pnas.2507535122

Experimental method

X-RAY DIFFRACTION (2.42 Å)