Conformational changes in serpins and the mechanism of α1-antitrypsin deficiency

Robin W. Carrell, James Whisstock, David A. Lomas

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13 Citations (Scopus)

Abstract

α1-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 β-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, Silyama) 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 lessen the accumulation of Z antitrypsin that is responsible for associated liver damage.

Original languageEnglish
Pages (from-to)S171-S175
Number of pages5
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume150
Issue number6 II
DOIs
Publication statusPublished - Dec 1994
Externally publishedYes

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