Identification of functionally important residues in TFPI Kunitz domain 3 required for the enhancement of its activity by protein S

被引：53

作者：

Ahnstroem, Josefin ^{[1
]}

Andersson, Helena M. ^{[1
]}

Hockey, Verity ^{[1
]}

Meng, Yiran ^{[1
]}

McKinnon, Thomas A. J. ^{[1
]}

Hamuro, Tsutomu ^{[2
]}

Crawley, James T. B. ^{[1
]}

Lane, David A. ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Ctr Haematol, Fac Med, London W12 0NN, England

[2] Chemoserotherapeut Res Inst, Kaketsuken, Japan

来源：

BLOOD | 2012年 / 120卷 / 25期

关键词：

FACTOR PATHWAY INHIBITOR; TISSUE FACTOR PATHWAY; FACTOR-XA INHIBITION; C COFACTOR FUNCTION; COAGULATION INHIBITOR; MECHANISM; TERMINUS; KINETICS;

D O I：

10.1182/blood-2012-05-432005

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Protein S is a cofactor for tissue factor pathway inhibitor (TFPI) that critically reduces the inhibition constant for FXa to below the plasma concentration of TFPI. TFPI Kunitz domain 3 is required for this enhancement to occur. To delineate the molecular mechanism underlying enhancement of TFPI function, in the present study, we produced a panel of Kunitz domain 3 variants of TFPI encompassing all 12 surface-exposed charged residues. Thrombin-generation assays in TFPI-epleted plasma identified a novel variant, TFPI E226Q, which exhibited minimal enhancement by protein S. This was confirmed in purified FXa inhibition assays in which no protein S enhancement of TFPI E226Q was detected. Surface plasmon resonance demonstrated concentration-dependent binding of protein S to wildtype TFPI, but almost no binding to TFPI E226Q. We conclude that the TFPI Kunitz domain 3 residue Glu226 is essential for TFPI enhancement by protein S. (Blood. 2012; 120(25): 5059-5062)

引用

页码：5059 / 5062

页数：4

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