哺乳动物细胞N-连接糖基化途径的集中模块性
Centralized Modularity of N-Linked Glycosylation Pathways in Mammalian Cells
摘要：
糖基化是一个高度复杂的过程，产生各种各样的细胞聚糖，这些聚糖附着在蛋白质和脂质上。聚糖参与基本的生物学过程，包括蛋白质折叠和清除、细胞增殖和凋亡、发育、免疫应答和发病机制。聚糖的主要类型之一，N-连接聚糖，是通过有限数量的酶将单糖顺序连接到蛋白质上形成的。这些酶中的许多可以接受多个N-连接聚糖作为底物，从而产生大量聚糖中间体及其混合途径。受复杂网络研究中发展的定量方法的启发，我们研究了哺乳动物细胞中这种N-连接糖基化途径的大规模组织。N-连接的糖基化途径是极其模块化的，并且由直接从聚糖合成的共同上游途径分支的内聚拓扑模块组成。这种独特的结构特性允许模块之间的聚糖生产由上游区域控制。尽管酶作用于多种聚糖底物，表明模块之间的串扰，但串扰对聚糖合成的模块特异性增强的影响可能被转录水平控制限制在中等范围内。本研究的结果提供了实验可测试的预测糖基化过程，并可能适用于治疗性糖蛋白工程。
英文摘要：
Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes, including protein folding and clearance, cell proliferation and apoptosis, development, immune responses, and pathogenesis. One of the major types of glycans, N-linked glycans, is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the large-scale organization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways are extremely modular, and are composed of cohesive topological modules that directly branch from a common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled by the upstream region. Although the enzymes act on multiple glycan substrates, indicating cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis may be confined within a moderate range by transcription-level control. The findings of the present study provide experimentally-testable predictions for glycosylation processes, and may be applicable to therapeutic glycoprotein engineering.
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