title: The shapes of Z-α1-antitrypsin polymers in solution support the C-terminal domain-swap mechanism of polymerization.
abstract: Emphysema and liver cirrhosis can be caused by the Z mutation (Glu342Lys) in the serine protease inhibitor α1-antitrypsin (α1AT), which is found in more than 4% of the Northern European population. Homozygotes experience deficiency in the lung concomitantly with a massive accumulation of polymers within hepatocytes, causing their destruction. Recently, it was proposed that Z-α1AT polymerizes by a C-terminal domain swap. In this study, small-angle x-ray scattering (SAXS) was used to characterize Z-α1AT polymers in solution. The data show that the Z-α1AT trimer, tetramer, and pentamer all form ring-like structures in strong support of a common domain-swap polymerization mechanism that can lead to self-terminating polymers.
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus, Denmark; iNANO Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark; Division of Physical Chemistry, Department of Chemistry, Lund University, Lund, Sweden.
authors.forename: Manja A
authors.initials: MA
authors.lastname: Behrens
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sendall
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus, Denmark; iNANO Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Department of Molecular Biology, and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Kjeldgaard
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Huntington
authors.affiliation: Department of Molecular Biology, and Genetics, Aarhus University, Aarhus, Denmark; Danish-Chinese Centre for Proteases and Cancer, Aarhus University, Aarhus, Denmark. Electronic address: jkj@mb.au.dk.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Jensen
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000515:alpha 1-Antitrypsin