A Systems Biology Approach for the Investigation of the Heparin/Heparan Sulfate Interactome
A Systems Biology Approach for the Investigation of the Heparin/Heparan Sulfate Interactome
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DOI：
10.1074/jbc.m111.228114
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发表时间：
2011-06-03
影响因子：
4.8
通讯作者：
Fernig, David G.
中科院分区：
文献类型：
--
作者：
Ori, Alessandro;Wilkinson, Mark C.;Fernig, David G.
大量证据支持硫酸乙酰肝素(HS)蛋白多糖参与生理过程，如发育和疾病，包括癌症和神经退行性疾病。HS的作用来自于其相互作用和调节大量细胞外蛋白质的活性，包括生长因子和细胞外基质成分。关于蛋白质-HS相互作用如何影响细胞外蛋白质组，从而影响细胞功能的全球观点目前还缺乏。在这里，我们系统地研究了HS相互作用蛋白及其形成的网络的功能和结构特性。通过整合文献来源和亲和蛋白质组学数据，我们收集了435个与HS或结构上相关的肝素相互作用的人类蛋白质。我们使用这个数据集来识别区分肝素/HS相互作用网络与其余细胞外蛋白质组的拓扑特征，并分析肝素/HS结合蛋白中基因本体论术语、途径和结构域家族的丰富。我们的分析表明，肝素/HS结合蛋白形成了一个高度互联的网络，该网络在功能上与高等生物特有的生理和病理过程相联系。因此，我们随后调查了后生动物血统中肝素/HS相互作用组域家族特征的扩展与生物复杂性增加之间的相关性。肝素/HS相互作用组的扩大与生物合成机制和生物体的复杂性之间出现了很强的正相关。在后生动物谱系的根部的单细胞有机体中，存在一种基本的HS生物合成机制，从而加强了HS的进化作用。
A large body of evidence supports the involvement of heparan sulfate (HS) proteoglycans in physiological processes such as development and diseases including cancer and neurodegenerative disorders. The role of HS emerges from its ability to interact and regulate the activity of a vast number of extracellular proteins including growth factors and extracellular matrix components. A global view on how protein-HS interactions influence the extracellular proteome and, consequently, cell function is currently lacking. Here, we systematically investigate the functional and structural properties that characterize HS-interacting proteins and the network they form. We collected 435 human proteins interacting with HS or the structurally related heparin by integrating literature-derived and affinity proteomics data. We used this data set to identify the topological features that distinguish the heparin/HS-interacting network from the rest of the extracellular proteome and to analyze the enrichment of gene ontology terms, pathways, and domain families in heparin/HS-binding proteins. Our analysis revealed that heparin/HS-binding proteins form a highly interconnected network, which is functionally linked to physiological and pathological processes that are characteristic of higher organisms. Therefore, we then investigated the existence of a correlation between the expansion of domain families characteristic of the heparin/HS interactome and the increase in biological complexity in the metazoan lineage. A strong positive correlation between the expansion of the heparin/HS interactome and biosynthetic machinery and organism complexity emerged. The evolutionary role of HS was reinforced by the presence of a rudimentary HS biosynthetic machinery in a unicellular organism at the root of the metazoan lineage.