New insights into the structural basis of α1,-antitrypsin deficiency

The serpin superfamily of serine proteinase inhibitors contains many members but the best-characterized is the plasma protein α1,-antitrypsin. Its genetic deficiency is associated, in the homozygote, with hepatic damage that may progress to cirrhosis and hepatocellular carcinoma. Low levels of circulating α1,-antitrypsin fail to protect the lungs against proteolytic attack and predispose the homozygote to early onset pan-lobular emphysema, bronchiectasis and asthma. The major cause of α1,-antitrypsin deficiency, the Z mutation (Glu342Lys), results in the accumulation of protein in the endoplasmic reticulum of the liver. Using a structural approach, we have shown that the hepatic inclusions result from a protein–protein interaction between the reactive centre loop of one molecule and the β -pleated sheet of a second. This loop-sheet polymerization is now also recognized to be the basis of deficiencies associated with mutations of C1-inhibitor, antithrombin and α1,-antichymotrypsin. Our recent solution of a crystal structure of a thermostable mutant of α1,-antitrypsin shows the detailed interactions that result in loop-sheet linkage and helps to explain the mechanism of action of this family of proteinase inhibitors.