Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase
Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase
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DOI：
10.1182/blood.v95.5.1714.005k40_1714_1720
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发表时间：
2000-03-01
期刊：
影响因子：
20.3
通讯作者：
Fay, PJ
中科院分区：
文献类型：
--
作者：
O'Brien, LM;Mastri, M;Fay, PJ
因子Villa是A1、A2和A3-C1-C2亚基的三聚体。人活化蛋白C（APC）对辅因子的失活是由于在A1亚基内的Arg 336处的优先切割，随后在平分A2亚基的Arg 562处的切割。在人蛋白S存在下，APC依赖性因子VIIIa失活的速率增加了几倍，并且与Arg 562处的切割速率增加相关，（活性位点修饰的）因子IXa，阻断A2位点的裂解。然而，APC催化的因子Villa的失活以与因子IXa无关的类似速率进行，这与A1亚基内的优先切割位点的位置一致。当存在因子IXa时，蛋白S的加入未能增加A2位点处的切割速率。在因子X的存在下，辅因子失活受到抑制，这是由于在Arg 336处的切割速率降低。然而，包含蛋白S恢复了因子Villa失活和在At位点处的切割的接近原始速率，从而克服了因子X依赖性保护作用。这些结果表明，在人类系统中，蛋白S通过促进A2亚基的切割刺激APC催化的因子VIIIa失活（在因子IXa的存在下延迟的作用），以及消除辅因子与因子X的保护性相互作用，（C）2000，美国血液学学会。
Factor Villa is a trimer of Al, A2, and A3-C1-C2 subunits. Inactivation of the cofactor by human activated protein C (APC) results from preferential cleavage at Arg336 within the Al subunit, followed by cleavage at Arg562 bisecting the A2 subunit, In the presence of human protein S, the rate of Ape-dependent factor VIIIa inactivation increased several-fold and correlated with an increased rate of cleavage at Arg562, (Active site-modified) factor IXa, blocked cleavage at the A2 site. However, APC-catalyzed inactivation of factor Villa proceeded at a similar rate independent of factor IXa, consistent with the location of the preferential cleavage site within the Al subunit, Addition of protein S failed to increase the rate of cleavage at the A2 site when factor IXa was present. In the presence of factor X, cofactor inactivation was inhibited, due to a reduced rate of cleavage at Arg336, However, inclusion of protein S restored near original rates of factor Villa inactivation and cleavage at the At site, thus overcoming the factor X-dependent protective effect, these results suggest that in the human system, protein S stimulates APC-catalyzed factor Villa inactivation by facilitating cleavage of A2 subunit (an effect retarded in the presence of factor IXa), as well as abrogating protective interactions of the cofactor with factor X, (C) 2000 by The American Society of Hematology.