Fibrillar amyloid beta-protein binds protease nexin-2/amyloid beta-protein precursor: stimulation of its inhibition of coagulation factor XIa.
Fibrillar amyloid beta-protein binds protease nexin-2/amyloid beta-protein precursor: stimulation of its inhibition of coagulation factor XIa.
复制标题
纤维状淀粉样β蛋白结合蛋白酶nexin-2/淀粉样β蛋白前体：刺激其抑制凝血因子XIa。
DOI：
10.1021/bi0002840
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发表时间：
2000
期刊：
影响因子：
2.9
通讯作者：
VanNostrand,WE
中科院分区：
文献类型：
--
作者：
Wagner,MR;Keane,DM;Melchor,JP;Auspaker,KR;VanNostrand,WE
脑血管纤维状39−42氨基酸淀粉样蛋白（a β）沉积，一种被称为脑淀粉样血管病（CAA）的疾病，是阿尔茨海默病和相关疾病的关键病理特征，包括遗传性脑出血伴淀粉样变性-荷兰型（HCHWA-D）。严重的CAA病例，特别是HCHWA-D，可导致复发性和经常致命的出血性中风。虽然这种病理结果的原因尚不清楚，但已涉及蛋白溶解止血机制的改变。例如，a β亲本分子蛋白酶连接蛋白-2/淀粉样β-蛋白前体（PN-2/ a β pp）在a β沉积的HCHWA-D脑血管中升高，是一种有效的凝血因子XIa （FXIa）抑制剂。在这里，我们发现原纤维HCHWA-D a β结合PN-2/ a - β pp，但不结合其分离的kunitz型蛋白酶抑制剂（KPI）结构域，以饱和、剂量依赖的方式与aKdof≈28 nM结合。PN-2/ a - β pp及其KPI结构域均未与非纤原性HCHWA-D a - β结合。PN-2/ a - β pp的纤维状Aβ结合域定位在残基18 ~ 119上。与固定在塑料孔或体外培养的脑血管平滑肌细胞表面的纤维状HCHWA-D Aβ结合的PN-2/ a - β pp具有抑制FXIa的活性。定量动力学测量显示，原纤维HCHWA-D a β可使PN-2/ a - β pp对FXIa的抑制作用增强约5倍。在原纤维野生型Aβ中，PN-2/ a - β pp对FXIa的抑制作用也有类似的刺激作用。而纤原Aβ对PN-2/Aβ pp对胰蛋白酶的抑制作用无明显影响。这些结果表明，纤维状a β沉积在脑血管中可以有效地定位和增强PN-2/ a - β pp的抗凝功能，从而形成有利于出血的微环境。
Cerebrovascular deposition of fibrillar 39−42 amino acid amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a key pathological feature of Alzheimer's disease and related disorders including hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). Severe cases of CAA, particularly in HCHWA-D, lead to recurrent and often fatal hemorrhagic strokes. Although the reasons for this pathological consequence remain unclear, alterations in proteolytic hemostasis mechanisms have been implicated. For example, the Aβ parent molecule protease nexin-2/amyloid β-protein precursor (PN-2/AβPP), which is elevated in HCHWA-D cerebral vessels with Aβ deposits, is a potent inhibitor of coagulation factor XIa (FXIa). Here we show that fibrillar HCHWA-D Aβ binds PN-2/AβPP, but not its isolated Kunitz-type proteinase inhibitor (KPI) domain, in a saturable, dose-dependent manner with aKdof ≈28 nM. Neither PN-2/AβPP nor its KPI domain bound to nonfibrillar HCHWA-D Aβ. The fibrillar Aβ binding domain on PN-2/AβPP was localized to residues 18−119. PN-2/AβPP that bound to fibrillar HCHWA-D Aβ immobilized either in plastic wells or on the surface of cultured cerebrovascular smooth muscle cells was active in inhibiting FXIa. Quantitative kinetic measurements revealed that fibrillar HCHWA-D Aβ caused a >5-fold enhancement of FXIa inhibition by PN-2/AβPP. Similar stimulatory effects on FXIa inhibition by PN-2/AβPP were also observed with fibrillar wild-type Aβ. However, fibrillar Aβ had no effect on the inhibition of trypsin by PN-2/AβPP. These findings suggest that fibrillar Aβ deposits in cerebral vessels can effectively localize and enhance the anticoagulant functions of PN-2/AβPP, thereby contributing to a microenvironment conducive to hemorrhaging.