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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis for ubiquitin and ISG15 crossreactivity in viral ovarian tumor domains
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Molecular basis for ubiquitin and ISG15 crossreactivity in viral ovarian tumor domains

机译：病毒性卵巢肿瘤域中泛素和ISG15交叉反应性的分子基础

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摘要

Crimean Congo hemorrhagic fever virus (CCHFV) is a deadly human pathogen that evades innate immune responses by efficiently interfering with antiviral signaling pathways mediated by NF-κB, IRF3, and IFNα/β. These pathways rely on protein ubiquitination for their activation, and one outcome is the modification of proteins with the ubiquitin (Ub)-like modifier interferon-stimulated gene (ISG)15. CCHFV and related viruses encode a deubiquitinase (DUB) of the ovarian tumor (OTU) family, which unlike eukaryotic OTU DUBs also targets ISG15 modifications. Here we characterized the viral OTU domain of CCHFV (vOTU) biochemically and structurally, revealing that it hydrolyzes four out of six tested Ub linkages, but lacks activity against linear and K29-linked Ub chains. vOTU cleaved Ub and ISG15 with similar kinetics, and we were able to understand vOTU cross-reactivity at the molecular level from crystal structures of vOTU in complex with Ub and ISG15. An N-terminal extension in vOTU not present in eukaryotic OTU binds to the hydrophobic Ile44 patch of Ub, which results in a dramatically different Ub orientation compared to a eukaryotic OTU-Ub complex. The C-terminal Ub-like fold of ISG15 (ISG15-C) adopts an equivalent binding orientation. Interestingly, ISG15-C contains an additional second hydrophobic surface that is specifically contacted by vOTU. These subtle differences in Ub/ISG15 binding allowed the design of vOTU variants specific for either Ub or ISG15, which will be useful tools to understand the relative contribution of ubiquitination vs. ISGylation in viral infection. Furthermore, the crystal structures will allow structure-based design of antiviral agents targeting this enzyme.
机译：克里米亚刚果出血热病毒（CCHFV）是一种致命的人类病原体，通过有效干扰NF-κB，IRF3和IFNα/β介导的抗病毒信号传导途径，逃避先天免疫反应。这些途径依赖于蛋白质泛素化来激活，而一种结果是利用泛素（Ub）样修饰因子干扰素刺激基因（ISG）对蛋白质进行修饰15。 CCHFV和相关病毒编码卵巢肿瘤（OTU）家族的去泛素酶（DUB），与真核OTU DUB不同，它也靶向ISG15修饰。在这里，我们从生化和结构上表征了CCHFV（vOTU）的病毒OTU结构域，揭示了它水解了6个测试的Ub连锁中的4个，但缺乏针对线性和K29连接的Ub链的活性。 vOTU以相似的动力学裂解Ub和ISG15，我们能够从vOTU与Ub和ISG15形成复合物的分子结构中了解vOTU在分子水平上的交叉反应性。真核OTU中不存在的vOTU中的N端延伸与Ub的疏水Ile44斑块结合，与真核OTU-Ub复合体相比，导致Ub方向显着不同。 ISG15（ISG15-C）的C端Ub样折叠采用等效的结合方向。有趣的是，ISG15-C包含一个额外的第二疏水表面，该表面与vOTU专门接触。 Ub / ISG15结合中的这些细微差异允许设计针对Ub或ISG15的vOTU变体，这将是了解泛素化与ISGylation在病毒感染中相对贡献的有用工具。此外，晶体结构将允许针对该酶的抗病毒剂进行基于结构的设计。

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  • 作者

    Masato Akutsu; Yu Ye; Satpal Virdee; Jason W. Chin; David Komander;

  • 作者单位

    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, United Kingdom;

    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, United Kingdom;

    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, United Kingdom;

    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, United Kingdom;

    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 OQH, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    cell signaling; structural biology; biochemistry; emerging disease;

    机译：细胞信号;结构生物学;生化;新兴疾病;

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