Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis
Ravi Mahadeva, … , Derek G.D. Wight, David A. Lomas
Ravi Mahadeva, … , Derek G.D. Wight, David A. Lomas
Published April 1, 1999
Citation Information: J Clin Invest. 1999;103(7):999-1006. https://doi.org/10.1172/JCI4874.
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Article

Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis

Abstract

The association between Z α1-antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z α1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S α1-antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z α1-antitrypsin and another conformationally unstable variant (I α1-antitrypsin; 39Arg→Cys) identified in a 34-year-old man with cirrhosis related to α1-antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z α1-antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.

Authors

Ravi Mahadeva, Wun-Shaing W. Chang, Timothy R. Dafforn, Diana J. Oakley, Richard C. Foreman, Jacqueline Calvin, Derek G.D. Wight, David A. Lomas

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Figure 7

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(a) The crystal structures of α1-antitrypsin (32, 33) demonstrated the a...
(a) The crystal structures of α1-antitrypsin (32, 33) demonstrated the availability of 232Cys and the position of the I (39Arg→Cys) mutation in helix A at the back of the molecule. The reactive center loop is shown in red; the A β-sheet, which must open to allow polymer formation, is illustrated in green. S α1-antitrypsin mediates its effect by breaking a hydrogen bond with 38Tyr in the shutter domain (20), which controls A β-sheet mobility. (b) Reactive loop/A-sheet polymerization with an open helical conformation (32) places the cysteine residues over 60 Å apart (right), but a closed helical conformation predictably brings the cysteine residues of different α1-antitrypsin molecules close to each other and therefore available for resonance energy transfer (left). In this model, the α1-antitrypsin molecules are ordered blue, green, and red (from bottom to top), with RET predictably occurring between the labeled cysteines of molecules of the same color.