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J. Biol. Chem., Vol. 268, Issue 21, 15333-15335, 07, 1993
DA Lomas, JT Finch, K Seyama, T Nukiwa and RW Carrell
Antitrypsin Siiyama is a rare example of the deficiency variants of
antitrypsin that accumulate in the endoplasmic reticulum of the hepatocyte.
The common example is Z antitrypsin, which has a mutation (Glu342-->Lys)
at the junction of the head of the fifth strand of the A sheet and the base
of the reactive center loop. It was previously shown that Z antitrypsin
spontaneously polymerizes due to the insertion of the reactive center loop
of one molecule into the A sheet of a second. The mutation in antitrypsin
Siiyama (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 this here and show that virtually all the
plasma antitrypsin in a homozygote for the Siiyama variant was polymerized
due to non-covalent bonding with a loss of accessibility of the reactive
center loop. The common basis of the polymerization of Z and Siiyama
antitrypsin is supported by identical findings on electron microscopy.
Taken together these results confirm that loop-sheet polymerization is a
general mechanism and as such is likely to be responsible for the
intracellular inclusions associated with liver pathology.
Alpha 1-antitrypsin Siiyama (Ser53-->Phe). Further evidence for intracellular loop-sheet polymerization
Department of Haematology, University of Cambridge, United Kingdom.
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