A3 类蜱 evasin EVA-ACA1001 识别趋化因子的结构基础。

IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Protein Science Pub Date : 2024-06-01 DOI:10.1002/pro.4999
Shankar Raj Devkota, Pramod Aryal, Matthew C J Wilce, Richard J Payne, Martin J Stone, Ram Prasad Bhusal
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引用次数: 0

摘要

蜱虫会在唾液中产生趋化因子结合蛋白,即 Evasins,以破坏宿主的免疫反应。evasins 与趋化因子结合,从而抑制其同源趋化因子受体的活化,从而抑制白细胞的募集和炎症反应。我们最近描述了 A3 亚类 evasins,与其他 A 类 evasins 一样,它们只针对 CC 趋化因子,但似乎使用不同的结合位点结构来控制 CC 趋化因子的目标选择性。我们现在描述 A3 类 evasin EVA-ACA1001 识别趋化因子的结构基础。EVA-ACA1001 几乎能与所有人类 CC 趋化因子结合,并抑制受体活化。EVA-ACA1001 的截短突变体表明,与 A1 类 evasins 不同,EVA-ACA1001 的 N 端和 C 端在趋化因子结合中的作用微乎其微。为了了解其广泛识别趋化因子的结构基础,我们测定了 EVA-ACA1001 与人类趋化因子 CCL16 复合物的晶体结构。EVA-ACA1001与CCL16的CC基团形成骨干-骨干相互作用,这是所有A类evasin-趋化因子复合物的保守特征。EVA-ACA1001 中的疏水口袋由几个芳香族侧链和 A3 类 evasins 独有的二硫键形成,可容纳紧随 CCL16 的 CC 基序之后的残基("CC + 1 残基")。这种相互作用与 EVA-AAM1001 共享,而 EVA-AAM1001 是迄今为止唯一具有特征的其他 A3 类 evasins,这表明它可能是 A3 类 evasins 广泛识别 CC 趋化因子的共同机制。
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Structural basis of chemokine recognition by the class A3 tick evasin EVA-ACA1001.

Ticks produce chemokine-binding proteins, known as evasins, in their saliva to subvert the host's immune response. Evasins bind to chemokines and thereby inhibit the activation of their cognate chemokine receptors, thus suppressing leukocyte recruitment and inflammation. We recently described subclass A3 evasins, which, like other class A evasins, exclusively target CC chemokines but appear to use a different binding site architecture to control target selectivity among CC chemokines. We now describe the structural basis of chemokine recognition by the class A3 evasin EVA-ACA1001. EVA-ACA1001 binds to almost all human CC chemokines and inhibits receptor activation. Truncation mutants of EVA-ACA1001 showed that, unlike class A1 evasins, both the N- and C-termini of EVA-ACA1001 play minimal roles in chemokine binding. To understand the structural basis of its broad chemokine recognition, we determined the crystal structure of EVA-ACA1001 in complex with the human chemokine CCL16. EVA-ACA1001 forms backbone-backbone interactions with the CC motif of CCL16, a conserved feature of all class A evasin-chemokine complexes. A hydrophobic pocket in EVA-ACA1001, formed by several aromatic side chains and the unique disulfide bond of class A3 evasins, accommodates the residue immediately following the CC motif (the "CC + 1 residue") of CCL16. This interaction is shared with EVA-AAM1001, the only other class A3 evasins characterized to date, suggesting it may represent a common mechanism that accounts for the broad recognition of CC chemokines by class A3 evasins.

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来源期刊
Protein Science
Protein Science 生物-生化与分子生物学
CiteScore
12.40
自引率
1.20%
发文量
246
审稿时长
1 months
期刊介绍: Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).
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