CONFORMATIONAL-CHANGES IN SERPINS AND THE MECHANISM OF ALPHA(1)-ANTITRYPSIN DEFICIENCY

alpha(1)-Antitrypsin is a member of the serine proteinase inhibitor, serpin, family of protease inhibitors, which have their reactive centers situated on a mobile peptide loop. This reactive loop can adopt varied conformations and perturbations of molecular structure to allow the pathological linking of the loop of one molecule to a beta-pleated sheet of another. This linkage has been shown to be the cause of the polymerization and aggregation within the hepatocyte of the common Z mutant of antitrypsin. The occurrence of loop-sheet polymerization has been confirmed with other deficiency variants of antitrypsin that accumulate in the liver (Mmalton, Siiyama) and also shown to occur in pathological mutants of C1-inhibitor and antithrombin. Deductive evidence indicates that the loop is inserted into the A-sheet of the next molecule, but recent structural findings raise the possibility of insertion into the C-sheet. This detail of loop-sheet polymerization is important for the design of strategies to interfere with insertion and hence lessen the accumulation of Z antitrypsin that is responsible for associated liver damage.