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Titolo:
IDENTIFICATION OF THROMBIN RESIDUES THAT MODULATE ITS INTERACTIONS WITH ANTITHROMBIN-III AND ALPHA-1-ANTITRYPSIN
Autore:
LEBONNIEC BF; GUINTO ER; STONE SR;
Indirizzi:
UNIV CAMBRIDGE,CTR MRC,DEPT HAEMATOL,HILLS RD CAMBRIDGE CB2 2QH ENGLAND
Titolo Testata:
Biochemistry
fascicolo: 38, volume: 34, anno: 1995,
pagine: 12241 - 12248
SICI:
0006-2960(1995)34:38<12241:IOTRTM>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN ALPHA-THROMBIN; HEPARIN COFACTOR-II; PLASMINOGEN-ACTIVATOR INHIBITOR-1; PRO-ARG CHLOROMETHYLKETONE; TIGHT-BINDING INHIBITORS; NEURITE-PROMOTING FACTOR; GLIA-DERIVED-NEXIN; PROTEIN-C; CRYSTAL-STRUCTURE; ANTI-THROMBIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
68
Recensione:
Indirizzi per estratti:
Citazione:
B.F. Lebonniec et al., "IDENTIFICATION OF THROMBIN RESIDUES THAT MODULATE ITS INTERACTIONS WITH ANTITHROMBIN-III AND ALPHA-1-ANTITRYPSIN", Biochemistry, 34(38), 1995, pp. 12241-12248

Abstract

The role of thrombin's catalytic groove in the interaction with serpin has been investigated by comparing the association rate constant (k(on)) of several mutated thrombins with various serpins. The results indicated that Glu(192), located three residues prior to the catalytic serine, and the major insertion in the sequence of thrombin compared with trypsin (residues Tyr(60A)-Trp(60D)) play an important role in modulating thrombin's interactions with serpins. Replacement of Glu(192) by glutamine increased by 3 orders of magnitude the k(on) value with alpha 1-antitrypsin (which has a P-1 methionine) but did not markedly alter the k(on) value with serpins containing a P-1 arginine. The des-PPW thrombin mutant (lacking residues pro(60B), Pro(60C), and Trp(60D)) exhibited a similar k(on) value as thrombin with protease nexin-1 but a k(on) value 2 orders of magnitude lower with antithrombin III. Thus,the 60-loop insertion of thrombin appears critical for its interaction with antithrombin III but dispensable for the formation of a complexwith protease nexin-1. Heparin increased markedly the k(on) values for antithrombin III and protease nexin-1 with all thrombin variants tested, but a more dramatic effect was observed with a thrombin mutant (des-ETW) lacking residues Glu(146), Thr(147), and Trp(148) (on the opposite side of the catalytic site relative to the 60-loop insertion). Atthe optimum concentration, heparin increased the k(on) value of the des-ETW-antithrombin III interaction by nearly 5 orders of magnitude, considerably more than for thrombin, suggesting that heparin is able tocompensate in part for the adverse effects of the des-ETW mutation onthe structure of thrombin.

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Documento generato il 13/07/20 alle ore 09:49:17