ALPHA-1-ANTITRYPSIN S(IIYAMA) (SER(53)-]PHE) - FURTHER EVIDENCE FOR INTRACELLULAR LOOP-SHEET POLYMERIZATION

Antitrypsin S(iiyama) is a rare example of the deficiency variants of antitrypsin that accumulate in the endoplasmic reticulum of the hepato cyte. The common example is Z antitrypsin, which has a mutation (Glu34 2 --> Lys) at the junction of the head of the fifth strand of the A sh eet and the base of the reactive center loop. It was previously shown that Z antitrypsin spontaneously polymerizes due to the insertion of t he reactive center loop of one molecule into the A sheet of a second. The mutation in antitrypsin S(iiyama)(Ser53 --> Phe) affects a residue that provides a ridge for the sliding movement that opens the A sheet , and it had been predicted that this would result in the same type of loop-sheet polymerization observed with the Z variant. We confirm thi s here and show that virtually all the plasma antitrypsin in a homozyg ote for the S(iiyama) variant was polymerized due to non-covalent bond ing with a loss of accessibility of the reactive center loop. The comm on basis of the polymerization of Z and S(iiyama) antitrypsin is suppo rted by identical findings on electron microscopy. Taken together thes e results confirm that loop-sheet polymerization is a general mechanis m and as such is likely to be responsible for the intracellular inclus ions associated with liver pathology.