title: A protein structural approach to the solution of biological problems: alpha 1-antitrypsin as a recent example.
abstract: 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.
authors.affiliation: Department of Haematology, University of Cambridge, United Kingdom.
authors.forename: D A
authors.initials: DA
authors.lastname: Lomas
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
mesh_terms: D000818:Animals; D003461:Crystallography; D006801:Humans; D008099:Liver / Q000378:metabolism; D009154:Mutation; D011108:Polymers / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
chemical_list: D011108:Polymers; D000515:alpha 1-Antitrypsin