title: New insights into the structural basis of alpha 1-antitrypsin deficiency.
abstract: The serpin superfamily of serine proteinase inhibitors contains many members but the best-characterized is the plasma protein alpha 1-antitrypsin. its genetic deficiency is associated, in the homozygote, with hepatic damage that may progress to cirrhosis and hepatocellular carcinoma. Low levels of circulating alpha 1-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 alpha 1-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 beta-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 alpha 1-antichymotrypsin. Our recent solution of a crystal structure of a thermostable mutant of alpha 1-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.
authors.affiliation: Department of Medicine, University of Cambridge, MRC Centre, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D008040:Genetic Linkage; D006801:Humans; D008107:Liver Diseases / Q000209:etiology; D008958:Models, Molecular; D015394:Molecular Structure; D017354:Point Mutation; D011487:Protein Conformation; D015843:Serpins / Q000737:chemistry; D000515:alpha 1-Antitrypsin / Q000737:chemistry; D019896:alpha 1-Antitrypsin Deficiency
chemical_list: D015843:Serpins; D000515:alpha 1-Antitrypsin