从鲍曼不动杆菌外毒素蛋白 F6W77 提取的 Kunitz-Domain 抗凝肽的特性。

IF 3.9 3区 医学 Q2 FOOD SCIENCE & TECHNOLOGY Toxins Pub Date : 2024-10-21 DOI:10.3390/toxins16100450
Fang Sun, Xiaolin Deng, Huanhuan Gao, Li Ding, Wen Zhu, Hongyi Luo, Xiangdong Ye, Xudong Luo, Zongyun Chen, Chenhu Qin
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引用次数: 0

摘要

最近的研究发现,凝血系统在哺乳动物的先天防御中发挥作用,它能将细菌夹在血凝块中,并产生抗菌肽。因此,抵御宿主凝血系统对细菌的生存非常重要,这表明细菌外毒素可能是抗凝剂的新来源。在这项研究中,我们分析了鲍曼不动杆菌的基因组序列,发现了一种新的细菌外毒素蛋白 F6W77,它具有五个 Kunitz 型结构域,即 KABP1-5。每个库尼茨型结构域都具有由三个保守二硫桥网状连接的经典六半胱氨酸框架,与动物库尼茨结构域多肽明显相似,但与植物库尼茨结构域多肽不同。抗凝血功能评价表明,对于内在凝血途径,KABP1和KABP5具有明显的抑制活性,KABP4具有微弱的抑制活性,而KBAP2和KABP3即使在20微克/毫升的高浓度下也没有作用。所有五种Kunitz-domain肽(KABP1-5)对外在凝血途径都没有抑制活性。酶抑制剂实验表明,高活性抗凝肽KABP1对两种关键凝血因子Xa和XIa具有明显的抑制活性,拉取实验进一步证实了这一点,该实验表明KABP1可直接与凝血因子Xa和XIa结合。对五个 Kunitz 型结构域多肽的结构-功能关系分析表明,KABP1、KABP4 和 KABP5 这三种新型细菌抗凝剂 P1 位点的精氨酸可能是其抗凝活性的关键残基。总之,通过生物信息学分析、多肽重组和功能评价,我们首次发现了细菌外毒素衍生的库尼茨型丝氨酸蛋白酶抑制剂,它们对固有凝血途径具有选择性抑制活性,凸显了致病细菌与人类凝血系统之间新的相互作用。
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Characterization of Kunitz-Domain Anticoagulation Peptides Derived from Acinetobacter baumannii Exotoxin Protein F6W77.

Recent studies have revealed that the coagulation system plays a role in mammalian innate defense by entrapping bacteria in clots and generating antibacterial peptides. So, it is very important for the survival of bacteria to defend against the host coagulation system, which suggests that bacterial exotoxins might be a new source of anticoagulants. In this study, we analyzed the genomic sequences of Acinetobacter baumannii and a new bacterial exotoxin protein, F6W77, with five Kunitz-domains, KABP1-5, was identified. Each Kunitz-type domain features a classical six-cysteine framework reticulated by three conserved disulfide bridges, which was obviously similar to animal Kunitz-domain peptides but different from plant Kunitz-domain peptides. Anticoagulation function evaluation showed that towards the intrinsic coagulation pathway, KABP1 and KABP5 had apparently inhibitory activity, KABP4 had weak inhibitory activity, and KBAP2 and KABP3 had no effect even at a high concentration of 20 μg/mL. All five Kunitz-domain peptides, KABP1-5, had no inhibitory activity towards the extrinsic coagulation pathway. Enzyme-inhibitor experiments showed that the high-activity anticoagulant peptide KABP1 had apparently inhibitory activity towards two key coagulation factors, Xa and XIa, which was further confirmed by pull-down experiments that showed that KABP1 can bind to coagulation factors Xa and XIa directly. Structure-function relationship analyses of five Kunitz-type domain peptides showed that the arginine of the P1 site of three new bacterial anticoagulants, KABP1, KABP4 and KABP5, might be the key residue for their anticoagulation activity. In conclusion, with bioinformatics analyses, peptide recombination, and functional evaluation, we firstly found bacterial-exotoxin-derived Kunitz-type serine protease inhibitors with selectively inhibiting activity towards intrinsic coagulation pathways, and highlighted a new interaction between pathogenic bacteria and the human coagulation system.

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来源期刊
Toxins
Toxins TOXICOLOGY-
CiteScore
7.50
自引率
16.70%
发文量
765
审稿时长
16.24 days
期刊介绍: Toxins (ISSN 2072-6651) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to toxins and toxinology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
期刊最新文献
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