Pathogen sensing by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is mediated by direct binding to muramyl dipeptide and ATP.
Pathogen sensing by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is mediated by direct binding to muramyl dipeptide and ATP.
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DOI：
10.1074/jbc.m112.344283
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发表时间：
2012-06-29
期刊：
影响因子：
--
通讯作者：
Duncan JA
中科院分区：
文献类型：
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作者：
Mo J;Boyle JP;Howard CB;Monie TP;Davis BK;Duncan JA
背景资料：含核苷酸结合和寡聚化结构域蛋白2（nucleotide binding and oligomerization domain-containing protein 2，NOD 2）是一种通过检测胞壁酰二肽参与细菌病原体识别的蛋白质。结果：纯化的重组NOD 2可与ATP和胞壁酰二肽结合。结论：NOD 2是胞壁酰二肽的细胞内信号受体。意义：这些结果有助于定义参与NOD 2信号传导的分子事件。含核苷酸结合和寡聚化结构域蛋白2（nucleotide binding and oligomerization domain-containing protein 2，NOD 2/Card 15）是一种细胞内蛋白，参与识别细菌细胞壁衍生的胞壁酰二肽。编码NOD 2的基因突变与遗传性炎症性疾病有关，包括克罗恩病和Blau综合征。NOD 2是核苷酸结合结构域和富含亮氨酸重复序列的蛋白质基因（NLR）家族的成员。核苷酸结合被认为在NLR家族成员的信号传导中起关键作用。然而，这些蛋白质的信号转导的分子机制在很大程度上仍然未知。NOD 2的核苷酸结合结构域中的突变已被证明在细胞测定中响应胞壁酰二肽而改变其信号转导特性。使用纯化的重组蛋白，我们现在证明NOD 2结合和水解ATP。此外，我们发现纯化的重组蛋白能够直接结合胞壁酰二肽，并能在体外与已知的NOD 2相互作用蛋白结合。NOD 2与胞壁酰二肽的结合和NOD 2的同源寡聚化通过ATP结合而增强，这表明了信号转导的分子机制的模型，其涉及核苷酸的结合，然后是胞壁酰二肽的结合和NOD 2寡聚化成信号复合物。这些发现为进一步研究胞壁酰二肽检测和含NOD 2信号复合物组装的分子机制奠定了基础。
Background: Nucleotide binding and oligomerization domain-containing protein 2 (NOD2) is a protein involved in the recognition of bacterial pathogens through detection of muramyl dipeptide. Results: Purified recombinant NOD2 was found to bind ATP and muramyl dipeptide. Conclusion: NOD2 is an intracellular signaling receptor for muramyl dipeptide. Significance: These results help to define the molecular events involved in NOD2 signaling. Nucleotide binding and oligomerization domain-containing protein 2 (NOD2/Card15) is an intracellular protein that is involved in the recognition of bacterial cell wall-derived muramyl dipeptide. Mutations in the gene encoding NOD2 are associated with inherited inflammatory disorders, including Crohn disease and Blau syndrome. NOD2 is a member of the nucleotide-binding domain and leucine-rich repeat-containing protein gene (NLR) family. Nucleotide binding is thought to play a critical role in signaling by NLR family members. However, the molecular mechanisms underlying signal transduction by these proteins remain largely unknown. Mutations in the nucleotide-binding domain of NOD2 have been shown to alter its signal transduction properties in response to muramyl dipeptide in cellular assays. Using purified recombinant protein, we now demonstrate that NOD2 binds and hydrolyzes ATP. Additionally, we have found that the purified recombinant protein is able to bind directly to muramyl dipeptide and can associate with known NOD2-interacting proteins in vitro. Binding of NOD2 to muramyl dipeptide and homo-oligomerization of NOD2 are enhanced by ATP binding, suggesting a model of the molecular mechanism for signal transduction that involves binding of nucleotide followed by binding of muramyl dipeptide and oligomerization of NOD2 into a signaling complex. These findings set the stage for further studies into the molecular mechanisms that underlie detection of muramyl dipeptide and assembly of NOD2-containing signaling complexes.