Pathogenic alpha 1-antitrypsin polymers are formed by reactive loop-beta-sheet A linkage.
J Biol Chem
; 275(43): 33663-8, 2000 Oct 27.
Article
in En
| MEDLINE
| ID: mdl-10924508
ABSTRACT
alpha(1)-Antitrypsin is the most abundant circulating protease inhibitor and the archetype of the serine protease inhibitor or serpin superfamily. Members of this family may be inactivated by point mutations that favor transition to a polymeric conformation. This polymeric conformation underlies diseases as diverse as alpha(1)-antitrypsin deficiency-related cirrhosis, thrombosis, angio-edema, and dementia. The precise structural linkage within a polymer has been the subject of much debate with evidence for reactive loop insertion into beta-sheet A or C or as strand 7A. We have used site directed cysteine mutants and fluorescence resonance energy transfer (FRET) to measure a number of distances between monomeric units in polymeric alpha(1)-antitrypsin. We have then used a combinatorial approach to compare distances determined from FRET with distances obtained from 2.9 x 10(6) different possible orientations of the alpha(1)-antitrypsin polymer. The closest matches between experimental FRET measurements and theoretical structures show conclusively that polymers of alpha(1)-antitrypsin form by insertion of the reactive loop into beta-sheet A.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alpha 1-Antitrypsin
Language:
En
Journal:
J Biol Chem
Year:
2000
Document type:
Article
Affiliation country:
United kingdom