The Shapes of Z-alpha(1)-Antitrypsin Polymers in Solution Support the C-Terminal Domain-Swap Mechanism of Polymerization
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Emphysema and liver cirrhosis can be caused by the Z mutation (Glu342Lys) in the serine protease inhibitor alpha 1-antitrypsin (alpha 1AT), 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-alpha 1AT polymerizes by a C-terminal domain swap. In this study, small-angle x-ray scattering (SAXS) was used to characterize Z-alpha 1AT polymers in solution. The data show that the Z-alpha 1AT 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.