AJP - Lung Cellular and Molecular Physiology, Vol 265, Issue 3 211-L219, Copyright © 1993 by American Physiological Society
A protein structural approach to the solution of biological problems: alpha 1-antitrypsin as a recent example
D. A. Lomas and R. W. Carrell
Department of Haematology, University of Cambridge, United Kingdom.
alpha 1-Antitrypsin is a circulating serine proteinase inhibitor that
protects the lungs against proteolysis by the enzyme neutrophil elastase.
Most northern Europeans have only the normal M form, but some 4% are
heterozygotes for the Z deficiency mutant. This mutant is characterized by
the substitution of a positively charged lysine residue for a negatively
charged glutamic acid at position 342 and results in normal gene
translation but reduced protein secretion into the plasma. The plasma
levels of antitrypsin in homozygotes are only 15% of normal, the other 85%
being retained in the endoplasmic reticulum of the hepatocyte. This review
describes the effect of the Z mutation on the structure and function of
antitrypsin and illustrates the importance of understanding protein
structure in solving the mechanism of Z antitrypsin retention within the
liver. We demonstrate that antitrypsin accumulation in the liver results
from a unique interaction between antitrypsin molecules. The Z mutation
perturbs the gap between the third and fifth strands of the A sheet,
allowing the reactive center loop of one molecule to insert into the A
sheet of a second. This loop-sheet polymerization results in the formation
of chains of protein which form insoluble inclusions in the endoplasmic
reticulum, resulting in hepatocellular damage and cirrhosis. In addition,
the Z mutation results in a distortion of the circular dichroic spectrum, a
rearrangement of the reactive center loop with respect to the A sheet, and
a reduction in association rate constant with the cognate proteinase
neutrophil elastase.
