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Intron structure of the human antithrombin III gene differs from that of other members of the serine protease inhibitor superfamily.

1985; Elsevier BV; Volume: 260; Issue: 17 Linguagem: Inglês

10.1016/s0021-9258(17)39280-3

1083-351X

EV Prochownik, S.C. Bock, Stuart H. Orkin,

Hemophilia Treatment and Research

Antithrombin I11 (ATIII) plays an integral role in the coagulation system by inhibiting thrombin and several other activated clotting factors.Inherited deficiency of ATIII is quite common and can result in life-threatening thrombotic complications.In order to understand the basis of ATIII deficiency, we have isolated and characterized the normal human ATIII gene from a recombinant Charon 4A bacteriophage genomic library.The ATIII gene contains six exons and five introns distributed over approximately 19 kilobases of DNA.The positions of introns in the ATIII gene were compared with other members of the serine protease inhibitor family which share 17-31% amino acid homology.When aligned to achieve maximal protein homology, only one of the ATIII introns corresponded to the four introns of rat angiotensinogen or human ulantitrypsin.Similarly, only one ATIII intron was homologous to the seven introns of chicken ovalbumin.We present two testable models to explain the discrepancy in intron positions among members of the serine protease inhibitor superfamily of genes.Antithrombin I11 (ATIII') is a glycoprotein of M, 60,000 which plays a central role in the homeostatic regulation of the coagulation system (1, 2).By binding to and inhibiting thrombin (1, 3), as well as several other activated clotting components (most notably factors IXa, XIa, and XIIa) (4-6), ATIII indirectly influences fibrin clot formation.The physiologic significance of this control pathway is seen in individuals with inherited ATIII deficiency, an autosomal dominant disorder, in whom reduced ATIII levels can result in lifethreatening thrombotic complications (1, 7).ATIII, along with al-antitrypsin (al-AT), ovalbumin, angiotensinogen, and a,-antichymotrypsin has been classified into a "serine protease inhibitor superfamily" of proteins based on shared amino acid and cDNA homologies (8-13), and it has been