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@ARTICLE{Aldobiyan:642771,
      author       = {Aldobiyan, Ibrahim and Elliston, Emma L. K. and
                      Heyer-Chauhan, Narinder and Arold, Stefan T. and Zhao,
                      Lingyun and Huntington, Brandon and Lowen, Sarah M. and
                      Orlova, Elena V. and Irving, James and Lomas, David A.},
      title        = {{T}he mechanism of pathogenic α 1 -antitrypsin aggregation
                      in the human liver},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {122},
      number       = {46},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {PUBDB-2025-05620},
      pages        = {e2507535122},
      year         = {2025},
      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.},
      cin          = {EMBL-User},
      ddc          = {500},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P14-20150101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1073/pnas.2507535122},
      url          = {https://bib-pubdb1.desy.de/record/642771},
}