Members of the serine proteinase inhibitor or serpin superfamily inhibit their target proteinases by a conformational transition that involves the enzyme being translocated more than 70 Angstroms from the upper to the lower pole of the inhibitor. This mechanism is subverted by point mutations to form ordered polymers that are retained within the endoplasmic reticulum of secretory cells. The accumulation of polymers underlies the retention of mutants of alpha(1)-antitrypsin and neuroserpin within hepatocytes and neurons to cause cirrhosis and dementia respectively. The formation of polymers results in the failure to secrete mutants of other members of the serpin superfamily: antithrombin, C1 inhibitor and alpha(1)-antichymotrypsin, to cause a plasma deficiency that results in the clinical syndromes of thrombosis, angio-oedema and emphysema respectively. Understanding the common mechanism underlying the retention and deficiency of mutants of the serpins has allowed the grouping of these conditions as the serpinopathies. Researchers are working on specific agents to block the polymerization that underlies disease. (Molecular mousetraps and the serpinopathies(1). Lomas DA, Belorgey D, et al. University of Cambridge, U.K. Biochem Soc Trans. 2005 Apr;33(Pt 2):321-30.)

Thomas E. Radecki, M.D., J.D.

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