Molecular basis of anticoagulant and anticomplement activity of the tick salivary protein Salp14 and its homologs.
Molecular basis of anticoagulant and anticomplement activity of the tick salivary protein Salp14 and its homologs.
复制标题
DOI：
10.1016/j.jbc.2021.100865
复制
发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Dijkgraaf I
中科院分区：
文献类型：
--
作者：
Denisov SS;Ippel JH;Castoldi E;Mans BJ;Hackeng TM;Dijkgraaf I
在进食过程中，蜱虫的口器穿透宿主的皮肤，破坏组织和小血管，触发外源性凝血和凝集素补体途径。为了避开这些防御机制，蜱虫在唾液中分泌多种抗凝血蛋白和补体系统抑制剂。在这里，我们表征了同源蜱唾液蛋白蜱唾液凝集素途径抑制剂Salp14和Salp9Pac在凝血级联和凝集素补体途径中的抑制活性。这三种蛋白均抑制甘露聚糖结合凝集素与甘露聚糖的结合，阻止凝集素补体途径的激活。相比之下，只有Salp14通过延长凝血酶产生的滞后时间而表现出明显的凝血作用。我们发现Salp14的抗凝特性受其基本尾部区域的控制，该区域类似于组织因子途径抑制剂α的C端，并以相同的方式阻断凝血酶原复合物的组装和/或活性。此外，Salp14蛋白尾部通过与甘露聚糖结合凝集素相关丝氨酸蛋白酶的相互作用，有助于抑制凝集素补体途径。此外，我们还鉴定了从鸟蜱中分离的baso4吸附蛋白1与蜱唾液凝集素途径抑制剂/Salp14蛋白具有远缘同源性，并表明其抑制凝集素补体途径，但不凝血。利用核磁共振光谱分析了baso4吸附蛋白1的结构，结果表明该蛋白具有非典型表皮生长因子结构域样结构褶皱，这是蜱虫唾液蛋白中首次报道的非典型表皮生长因子结构域。这些数据支持蜱虫唾液蛋白同时抑制宿主凝血级联和凝集素补体途径的机制。
During feeding, a tick's mouthpart penetrates the host's skin and damages tissues and small blood vessels, triggering the extrinsic coagulation and lectin complement pathways. To elude these defense mechanisms, ticks secrete multiple anticoagulant proteins and complement system inhibitors in their saliva. Here, we characterized the inhibitory activities of the homologous tick salivary proteins tick salivary lectin pathway inhibitor, Salp14, and Salp9Pac from Ixodesscapularis in the coagulation cascade and the lectin complement pathway. All three proteins inhibited binding of mannan-binding lectin to the polysaccharide mannan, preventing the activation of the lectin complement pathway. In contrast, only Salp14 showed an appreciable effect on coagulation by prolonging the lag time of thrombin generation. We found that the anticoagulant properties of Salp14 are governed by its basic tail region, which resembles the C terminus of tissue factor pathway inhibitor alpha and blocks the assembly and/or activity of the prothrombinase complex in the same way. Moreover, the Salp14 protein tail contributes to the inhibition of the lectin complement pathway via interaction with mannan binding lectin–associated serine proteases. Furthermore, we identified BaSO4-adsorbing protein 1 isolated from the tick Ornithodoros savignyi as a distant homolog of tick salivary lectin pathway inhibitor/Salp14 proteins and showed that it inhibits the lectin complement pathway but not coagulation. The structure of BaSO4-adsorbing protein 1, solved here using NMR spectroscopy, indicated that this protein adopts a noncanonical epidermal growth factor domain–like structural fold, the first such report for tick salivary proteins. These data support a mechanism by which tick saliva proteins simultaneously inhibit both the host coagulation cascade and the lectin complement pathway.
登录
查看更多内容
影响因子：
4.8
作者：
Lu, HS;Chai, JJ;Bi, RC
通讯作者：
Bi, RC
影响因子：
5.7
作者：
Kazimírová M;Štibrániová I
通讯作者：
Štibrániová I
影响因子：
2.2
作者：
Horak, IG;Camicas, JL;Keirans, JE
通讯作者：
Keirans, JE
影响因子：
5.4
作者：
Keizer, Mischa P.;Pouw, Richard B.;Wouters, Diana
通讯作者：
Wouters, Diana
影响因子：
4.8
作者：
Mans, BJ;Louw, AI;Neitz, AWH
通讯作者：
Neitz, AWH