Computational predictions of cysteine cathepsin-mediated fibrinogen proteolysis
Computational predictions of cysteine cathepsin-mediated fibrinogen proteolysis
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DOI：
10.1002/pro.3366
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Platt, Manu O.
中科院分区：
文献类型：
--
作者：
Ferrall-Fairbanks, Meghan C.;West, Dayne M.;Platt, Manu O.
纤维蛋白原凝块形成是凝血酶和纤溶酶分别被鉴定为裂解纤维蛋白原前体和纤维蛋白原聚合物的主要蛋白酶的事件的蛋白水解级联。其他蛋白酶可能直接参与纤维蛋白（原）切割、凝块形成和分解，或参与作为组织工程构建体的有用工具出现的基于纤维蛋白的支架的降解。在这里，半胱氨酸组织蛋白酶被调查的推定能力，水解纤维蛋白原，因为他们是有效的蛋白酶，首先确定在溶酶体蛋白质降解和已知参与细胞外蛋白水解。为了进一步探索这一点，我们使用了两个独立的计算技术，分子对接和生物信息学序列分析（PACMANS），预测潜在的结合相互作用和水解位点之间的组织蛋白酶K，L和S和纤维蛋白原。通过比较这两种客观计算方法的结果，确定组织蛋白酶K、L和S确实在相似且独特的位点结合并切割纤维蛋白原、和链。这些差异通过与每种组织蛋白酶单独孵育后独特的裂解纤维蛋白原带型实验可视化。总之，人半胱氨酸组织蛋白酶K，L和S是一类新的蛋白酶，应考虑在纤维蛋白（原）降解研究的疾病过程中，凝血是一个问题，也在生物工程系统的实施和设计。
Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as the main proteases cleaving fibrinogen precursor, and the fibrin polymer, respectively. Other proteases may be involved directly in fibrin(ogen) cleavage, clot formation, and resolution, or in the degradation of fibrin-based scaffolds emerging as useful tools for tissue engineered constructs. Here, cysteine cathepsins are investigated for their putative ability to hydrolyze fibrinogen, since they are potent proteases, first identified in lysosomal protein degradation and known to participate in extracellular proteolysis. To further explore this, we used two independent computational technqiues, molecular docking and bioinformatics sequence analysis (PACMANS), to predict potential binding interactions and sites of hydrolysis between cathepsins K, L, and S and fibrinogen. By comparing the results from these two objective, computational methods, it was determined that cathepsins K, L, and S do bind and cleave fibrinogen , , and chains at similar and unique sites. These differences were visualized experimentally by the unique cleaved fibrinogen banding patterns after incubation with each of the cathepsins, separately. In conclusion, human cysteine cathepsins K, L, and S are a new class of proteases that should be considered during fibrin(ogen) degradation studies both for disease processes where coagulation is a concern, and also in the implementation and design of bioengineered systems.