Conformational changes in serpins and the mechanism of alpha 1-antitrypsin deficiency.
alpha 1-Antitrypsin is a member of the serine proteinase inhibitor, serpin, family of protease inhibitors, which have their reactive centers situated on a mobile peptide loop. This reactive loop can adopt varied conformations and perturbations of molecular structure to allow the pathological linking of the loop of one molecule to a beta-pleated sheet of another. This linkage has been shown to be the cause of the polymerization and aggregation within the hepatocyte of the common Z mutant of antitrypsin. The occurrence of loop-sheet polymerization has been confirmed with other deficiency variants of antitrypsin that accumulate in the liver (Mmalton, Siiyama) and also shown to occur in pathological mutants of C1-inhibitor and antithrombin. Deductive evidence indicates that the loop is inserted into the A-sheet of the next molecule, but recent structural findings raise the possibility of insertion into the C-sheet. This detail of loop-sheet polymerization is important for the design of strategies to interfere with insertion and hence lesson the accumulation of Z antitrypsin that is responsible for associated liver damage.
Carrell
R W
RW
Department of Haematology, University of Cambridge, United Kingdom.
Whisstock
J
J
Lomas
D A
DA
D006801:Humans; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D010641:Phenotype; D011108:Polymers; D011487:Protein Conformation; D015843:Serpins / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency
D011108:Polymers; D015843:Serpins