Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin. (updated: April 1, 2015)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
This protein is annotated as membranous in Gene Ontology.
Total structural coverage: 95%
No model available.
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The reference OMIM entry for this protein is 107300
Serpin peptidase inhibitor, clade c (antithrombin), member 1; serpinc1
Antithrombin iii; at3
Antithrombin
Heparin cofactor i
DESCRIPTION
Antithrombin III is the most important inhibitor of thrombin (
176930) and other coagulation proteinases. It belongs to the serine proteinase inhibitor (serpin) superfamily of inhibitors and structurally related proteins, which contain reactive centers that have evolved to attract and entrap certain proteinases. Inherited antithrombin III deficiency (AT3D;
613118) is a risk factor for the early development of venous thromboembolism (THPH7) (summary by Lane et al., 1994). Antithrombin III regulates clot formation both by inhibiting thrombin activity directly and by interfering with earlier stages of the clotting cascade. Rosenberg and Bauer (1987) gave an excellent review of defects in the anticoagulant systems. They wrote as follows: 'The coagulation cascade can be pictured as a series of reactions in which a zymogen, a cofactor, and a converting enzyme interact to form a multimolecular complex on a natural surface. In each case, the 4 reactants must be present if the conversion of a zymogen to the corresponding serine protease is to take place at any significant rate. The principal natural anticoagulant systems that are able to exert damping effects on the various steps of the cascade are the heparin-antithrombin and protein C-thrombomodulin mechanisms that regulate the serine proteases and the cofactors or activated cofactors, respectively.'
CLONING
Bock et al. (1982) cloned an AT3 cDNA from a human liver cDNA library. Bjork et al. (1981, 1982) also cloned and characterized the AT3 gene, which encodes a deduced mature secreted peptide of 432 amino acids, 6 of which are cysteines forming 3 disulfide bonds. The protein has 4 glycosylation sites. It is synthesized with a 32-residue leader sequence cleaved prior to its secretion from the hepatocyte into the blood. The protein contains 2 important functional domains, the reactive center and the glycosaminoglycan-binding site. The reactive center is located near the C terminus, with the proteinase target cleavage site on the inhibitor at arg393-ser394. The glycosaminoglycan-binding region is located in the N terminus and is involved in the interaction with heparin and certain endothelial cell surface heparan sulfate proteoglycans. The reactive center and the heparin-binding site are conformationally linked; induced perturbations of one may influence the function of the other (summary by Lane et al., 1994).
GENE STRUCTURE
The AT3 gene has 7 exons. It contains 9 complete and 1 partial repetitive ALU sequence elements, which occur in the introns of the gene at a higher frequency (about 22% of the intron sequence) than in the genome as a whole (about 5%) (Chandra et al., 1983; Olds et al., 1993).
MAPPING
Using a purified cDNA probe of the AT3 gene and a series of human/Chinese hamster cell hybrids, Kao et al. (1984) assigned the gene to chromosome 1 by Southern blot analysis. Kao et al. (1984) assigned the AT3 gene to 1p31.3-qter. By in situ hybridization and quantitative analysis of DNA dosage in carriers of chromosome 1 deletions, Bock et al. (1985) assigned AT3 to 1q23-q25. Pakstis et al. (1989) reported linkage data between AT3 and the anonymous DNA fragment D1S75 (maximum lod score = 4.67 at theta = 11.4). In a linkage map of chromosome 1 prepared by Rouleau et al. (1990), it was concluded that AT3 lies about 17 cM distal to FY (
110700).
MOLECULAR GENETICS
Prochownik et al. (1983) found deletion of the AT3 gene in affected m ...
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Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 107300 was added.
Jan. 27, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed