Antitrypsin polymerization

Lomas, D.A., Mahadeva, R. Alpha(l)-antitrypsin polymerization and the serpinopathies pathobiology and prospects for therapy (review). J. Clin. Invest. 2002 110 1585-1590... 

Sequencing of the human dj-antitrypsin gene in 1984 initiated an explosion in the study of this disease. Transgenic mice were created to study the effects of dj-anti trypsin deficiency, and cell culture studies of the regulation of the gene became possible. In 1992, D. A. Lomas and colleagues (Lomas et al., 1992) showed that the accumulation of abnormal dj-antitrypsin in the ER of the liver was the result of polymerization of dj-antitrypsin.This discovery set the stage for the study of the effects of this polymerized material on the liver, which it is hoped will allow the mechanism of liver disease associated with dj-antitrypsin deficiency to be determined. 

Lomas DA, Elliott PR> Sidhar SK, Foreman RC> Finch JT, Cox DW, et al. al-Antitrypsin Mmalton (Phe52-deleted) forms loop-sheet polymers in vivo Evidence for the C sheet mechanism of polymerization. J Biol Chem 1995 270 16864-70. 

Lomas D. Loop-sheet polymerization The mechanism of alpha]-antitrypsin deficiency. Respir Med 2000 94 Suppl C S3-6. 

Simple systems (with a single defined additive) were produced with each of the following materials. Calf thymus DNA, polymerized, was obtained from Sigma. Protein sources were prepared in-house and subsequently dialyzed into low salt solutions. Human serum albumin and immunoglobulin G (IgG) were plasma-derived. Human immunoglobulin M (IgM) was produced by tissue culture fermentation and purified. A defined complex system consisted of both albumin and IgM together. An undefined complex system was set up with an intermediate material of Cohn plasma fractionation containing alpha-1 antitrypsin (alpha-1), albumin, and other contaminants. 

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