Plasma free fatty acid levels influence Zn(2+) -dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin.
Plasma free fatty acid levels influence Zn(2+) -dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin.
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DOI：
10.1111/jth.12771
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Stewart AJ
中科院分区：
文献类型：
--
作者：
Kassaar O;Schwarz-Linek U;Blindauer CA;Stewart AJ
富组氨酸糖蛋白（HRG）通过其结合和中和肝素的能力调节凝血。HRG与Zn2+结合刺激HRG -肝素复合物的形成。在正常情况下，大部分血浆Zn2+与人血清白蛋白（HSA）结合。然而，游离脂肪酸（FFAs）变构破坏Zn2+与HSA的结合。因此，与糖尿病、肥胖和癌症相关的高水平循环游离脂肪酸可能会增加与HRG相关的血浆Zn2+的比例，从而增加血栓性疾病的风险。为了表征HRG对Zn2+的结合，研究FFAs对HSA对Zn2+结合的影响，并确定ffa介导的Zn2+从HSA中位移是否会影响HRG -肝素复合物的形成。采用等温滴定量热法（ITC）检测不同FFA（肉豆酸酯）浓度下Zn2+与HRG和HSA的结合情况，采用ITC和ELISA检测不同Zn2+浓度下HRG -肝素复合物的形成情况。我们发现HRG具有10个Zn2+位点（K′= 1.63 × 105），并且FFA与HSA的累积结合干扰了其结合Zn2+的能力。Zn2+的结合也增加了HRG与未分离肝素相互作用的亲和力，但对其与低分子量肝素（~ 6850 Da）的相互作用没有影响。[2014年12月1日首次在线发布后补充更正：前一句“6850 kDa”更正为“6850 Da”。]基于所获得数据的血浆Zn2+形态模型表明，在血浆FFA水平高的个体中，FFA介导的血清白蛋白中Zn2+的位移可能会导致血栓并发症的发生。
Histidine-rich glycoprotein (HRG) regulates coagulation through its ability to bind and neutralize heparins. HRG associates with Zn2+ to stimulate HRG–heparin complex formation. Under normal conditions, the majority of plasma Zn2+ associates with human serum albumin (HSA). However, free fatty acids (FFAs) allosterically disrupt Zn2+ binding to HSA. Thus, high levels of circulating FFAs, as are associated with diabetes, obesity, and cancer, may increase the proportion of plasma Zn2+ associated with HRG, contributing to an increased risk of thrombotic disease. To characterize Zn2+ binding by HRG, examine the influence that FFAs have on Zn2+ binding by HSA, and establish whether FFA-mediated displacement of Zn2+ from HSA may influence HRG–heparin complex formation. Zn2+ binding to HRG and to HSA in the presence of different FFA (myristate) concentrations were examined by isothermal titration calorimetry (ITC) and the formation of HRG–heparin complexes in the presence of different Zn2+ concentrations by both ITC and ELISA. We found that HRG possesses 10 Zn2+ sites (K′ = 1.63 × 105) and that cumulative binding of FFA to HSA perturbed its ability to bind Zn2+. Also Zn2+ binding was shown to increase the affinity with which HRG interacts with unfractionated heparins, but had no effect on its interaction with low molecular weight heparin (˜ 6850 Da). [Correction added on 1 December 2014, after first online publication: In the preceding sentence, “6850 kDa” was corrected to “6850 Da”.] Speciation modeling of plasma Zn2+ based on the data obtained suggests that FFA-mediated displacement of Zn2+ from serum albumin would be likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels.
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DOI：
10.3181/00379727-203-43626
发表时间：
1993-09-01
影响因子：
--
作者：
EMERY, MP;ODELL, BL
通讯作者：
ODELL, BL
影响因子：
20.3
作者：
Kassaar, Omar;McMahon, Stephen A.;Stewart, Alan J.
通讯作者：
Stewart, Alan J.
影响因子：
6.5
作者：
ENGESSER, L;KLUFT, C;BROMMER, EJP
通讯作者：
BROMMER, EJP
影响因子：
4.8
作者：
Jones, AL;Hulett, MD;Parish, CR
通讯作者：
Parish, CR
影响因子：
7.1
作者：
GORDON, PR;WOODRUFF, CW;ODELL, BL
通讯作者：
ODELL, BL