Crystal structure of NOD2 and its implications in human disease.
Crystal structure of NOD2 and its implications in human disease.
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NOD2的晶体结构及其对人类疾病的影响。
DOI：
10.1038/ncomms11813
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发表时间：
2016-06-10
影响因子：
16.6
通讯作者：
Shimizu T
中科院分区：
文献类型：
--
作者：
Maekawa S;Ohto U;Shibata T;Miyake K;Shimizu T
核苷酸结合寡聚化结构域蛋白2 （NOD2）是nod样受体家族的一员，在先天免疫应答中起着至关重要的作用。NOD2突变与慢性炎症性疾病如克罗恩病（CD）、布劳综合征（BS）和早发性结节病（EOS）有关，但对其信号传导机制及其在这些疾病中的作用知之甚少。本文报道了兔NOD2在adp结合状态下的晶体结构。该结构揭示了一种非活性封闭构象，其中NOD结构域的子结构域被adp介导的和结构域间的相互作用紧密包裹。对BS-或eos -相关的功能获得突变的映射显示，这些突变大多数位于NOD子结构域界面，并且可能破坏内部结构域的相互作用，促进构象变化到活性形式。相反，与CD相关的突变分布在整个蛋白质中，其中一些突变可能影响低聚物的形成和配体的结合。NOD2在宿主先天免疫应答中起作用，激活NF-κB信号通路，其突变与慢性炎性疾病有关。在这里，Maekawa等人解析了NOD2非活性形式的结构，提出了一种自抑制机制。
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a member of the NOD-like receptors family, are crucial for innate immune responses. Mutations of NOD2 have been associated with chronic inflammatory disorders such as Crohn's disease (CD), Blau syndrome (BS) and early-onset sarcoidosis (EOS), but little is known about its signalling mechanism and the role it plays in these diseases. Here, we report the crystal structure of rabbit NOD2 in an ADP-bound state. The structure reveals an inactive closed conformation in which the subdomains in the NOD domain are closely packed by ADP-mediated and inter-domain interactions. Mapping of the BS- or EOS-associated gain-of-function mutations reveals that most of these mutations are located in the NOD subdomain interfaces, and are likely to disrupt the inner domain interactions, facilitating a conformational change to the active form. Conversely, mutations associated with CD are distributed throughout the protein, some of which may affect oligomer formation and ligand binding. NOD2 has a role in host innate immune responses, activating the NF-κB signalling pathway and mutations have been associated with chronic inflammatory disorders. Here, Maekawa et al. solved the structure of NOD2 in its inactive form, suggesting a mechanism for autoinhibition.