Matthew Y Otsuka,Leslie B Essel,Ashis Sinha,Gabrielle Nickerson,Seth M Mejia,Ashley Edge,Russell T Matthews,Samuel Bouyain
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引用次数: 0
摘要
Aggrecan(ACAN)是一种大型分泌型硫酸软骨素蛋白多糖,包括三个名为 G1、G2 和 G3 的球状区域,其 G2 和 G3 结构域之间有多个糖胺聚糖附着物。G1 区域的 N 端与糖胺聚糖透明质酸(HA)相互作用,后者是脊椎动物细胞外基质的重要组成部分。在中枢神经系统中,ACAN 存在于神经元周围网(PNN)中,这种蜂巢状结构定位在特定神经回路中副发光素阳性神经元的表面。PNNs 调节中枢神经系统的可塑性,人们认为 ACAN 和 HA 之间的关联是这些网状结构组装的基础事件。在此,我们报告了 ACAN G1 区在没有 HA 十糖和有 HA 十糖的情况下的共晶体结构,并分析了 ACAN 的 HA 结合活性对其整合到 PNNs 的重要性。我们证明,组成 G1 区域的单个免疫球蛋白结构域和两个 Link 模块形成了一个结构单元,HA 被夹在一个横跨串联 Link 结构域长度的沟槽内。在糖胺聚糖结合位点引入点突变会消除 ACAN 中的 HA 结合活性,但令人惊讶的是,这只会降低 ACAN 与 PNN 的整合。因此,这些结果表明,ACAN 可以独立于其 HA 结合活性而被招募到 PNN 中。
Aggrecan immobilizes to perineuronal nets through hyaluronan-dependent and independent binding activities.
Aggrecan (ACAN) is a large, secreted chondroitin sulfate proteoglycan that includes three globular regions named G1, G2, G3, and is decorated with multiple glycosaminoglycan attachments between its G2 and G3 domains. The N-terminal G1 region interacts with the glycosaminoglycan hyaluronan (HA), which is an essential component of the vertebrate extracellular matrix. In the central nervous system, ACAN is found in perineuronal nets (PNNs), honeycomb-like structures that localize to the surface of parvalbumin-positive neurons in specific neural circuits. PNNs regulate the plasticity of the central nervous system, and it is believed that association between ACAN and HA is a foundational event in the assembly of these reticular structures. Here, we report the co-crystal structure of the G1 region of ACAN in the absence and presence of a HA decasaccharide and analyze the importance of the HA-binding activity of ACAN for its integration into PNNs. We demonstrate that the single immunoglobulin domain and the two Link modules that comprise the G1 region form a single structural unit, and that HA is clamped inside a groove that spans the length of the tandem Link domains. Introducing point mutations in the glycosaminoglycan-binding site eliminates HA-binding activity in ACAN, but, surprisingly, only decreases the integration of ACAN into PNNs. Thus, these results suggest that ACAN can be recruited into PNNs independently of its HA-binding activity.
期刊介绍:
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