Understanding diversity of human innate immunity receptors: analysis of surface features of leucine-rich repeat domains in NLRs and TLRs.
Understanding diversity of human innate immunity receptors: analysis of surface features of leucine-rich repeat domains in NLRs and TLRs.
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DOI：
10.1186/1471-2172-10-48
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发表时间：
2009-09-03
期刊：
影响因子：
3
通讯作者：
Godzik A
中科院分区：
文献类型：
--
作者：
Istomin AY;Godzik A
人类先天性免疫系统使用细胞外Toll样受体（TLR）和细胞内Nod样受体（NLR）的系统来将适当水平的免疫应答与来自当前环境的威胁水平相匹配。几乎所有的NLR和TLR都具有由多个富含亮氨酸的重复序列（LRR）组成的结构域，其被认为参与配体结合。LRR也存在于数千种其他蛋白质中，形成了一个定义明确的“马蹄”形结构支架，可用于各种功能，从结合特定配体到执行一般结构角色。因此，LRR结构域在NLR和TLR中的特定功能作用由其详细的表面特征定义。虽然已经解决了四种人类TLR的实验晶体结构，但没有NLR的结构数据。我们报告了一个定量的，比较分析的LRR域的表面特征，在人类NLR和TLR，使用预测的三维结构的NLR。具体而言，我们计算了氨基酸的疏水性，电荷和糖基化分布在LRR结构域表面，并通过聚类评估其相似性。尽管在结构和基因组组织的差异，比较LRR表面功能的NLR和TLR允许我们假设他们可能的功能相似性。我们发现预测的表面相似性和类似的功能作用，在NLR和TLR与已知的激动剂之间的协议，并建议可能的结合伙伴的未表征的NLR。尽管它的分辨率低，我们的方法允许在没有晶体结构数据的情况下比较分子表面特征。我们的研究结果说明了先天免疫受体的表面特征的多样性，并提供提示的功能，其在先天免疫中的具体作用是未知的。
The human innate immune system uses a system of extracellular Toll-like receptors (TLRs) and intracellular Nod-like receptors (NLRs) to match the appropriate level of immune response to the level of threat from the current environment. Almost all NLRs and TLRs have a domain consisting of multiple leucine-rich repeats (LRRs), which is believed to be involved in ligand binding. LRRs, found also in thousands of other proteins, form a well-defined "horseshoe"-shaped structural scaffold that can be used for a variety of functions, from binding specific ligands to performing a general structural role. The specific functional roles of LRR domains in NLRs and TLRs are thus defined by their detailed surface features. While experimental crystal structures of four human TLRs have been solved, no structure data are available for NLRs. We report a quantitative, comparative analysis of the surface features of LRR domains in human NLRs and TLRs, using predicted three-dimensional structures for NLRs. Specifically, we calculated amino acid hydrophobicity, charge, and glycosylation distributions within LRR domain surfaces and assessed their similarity by clustering. Despite differences in structural and genomic organization, comparison of LRR surface features in NLRs and TLRs allowed us to hypothesize about their possible functional similarities. We find agreement between predicted surface similarities and similar functional roles in NLRs and TLRs with known agonists, and suggest possible binding partners for uncharacterized NLRs. Despite its low resolution, our approach permits comparison of molecular surface features in the absence of crystal structure data. Our results illustrate diversity of surface features of innate immunity receptors and provide hints for function of NLRs whose specific role in innate immunity is yet unknown.
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