Deciphering the Fringe-Mediated Notch Code: Identification of Activating and Inhibiting Sites Allowing Discrimination between Ligands.
Deciphering the Fringe-Mediated Notch Code: Identification of Activating and Inhibiting Sites Allowing Discrimination between Ligands.
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解密边缘介导的凹口代码：识别激活和抑制位点，允许歧视配体之间。
DOI：
10.1016/j.devcel.2016.12.013
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发表时间：
2017-01-23
影响因子：
11.8
通讯作者：
Haltiwanger RS
中科院分区：
文献类型：
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作者：
Kakuda S;Haltiwanger RS
边缘蛋白是 β3-N-乙酰氨基葡萄糖转移酶，通过修饰 Notch 的表皮生长因子样 (EGF) 重复序列上的 O-岩藻糖残基来调节 Notch 活性。哺乳动物有三种边缘：疯狂、狂躁和激进。 Lunatic 和 Manic Fringe 抑制 Jagged1 的 Notch1 激活并增强 Delta-like 1 的激活，而 Radical Fringe 则增强两者的信号传导。我们使用质谱方法来确定 Fringes 对 Notch1 的可变影响是否是由于 Notch1 上独特的糖基化模式的生成所致。我们发现 Lunatic 和 Manic Fringe 修改了 Notch1 上的相似位点，而 Radical Fringe 修改了一个子集。 EGF8 和 12 的边缘修饰增强了 Notch1 与 Delta-like 1 的结合和激活，而 EGF6 和 36 的修饰（由 Manic 和 Lunatic 添加，但不是 Radical）抑制了 Jagged1 的 Notch1 激活。综合起来，这些结果表明，Fringe 修饰“标记”了 Notch1 胞外域中的不同区域以进行激活或抑制。 Kakuda 和 Haltiwanger 研究了 Fringes 如何调节 Notch1。他们表明 Radical Fringe 修饰了由 Lunatic 和 Manic Fringe 修饰的 EGF 重复序列的子集。不同 EGF 重复序列的修饰会“标记”Notch1 胞外结构域，从而增强或抑制活性。
Fringe proteins are β3-N-acetylglucosaminyltransferases that modulate Notch activity by modifying O-fucose residues on Epidermal Growth Factor-like (EGF) repeats of Notch. Mammals have three Fringes: Lunatic, Manic, and Radical. While Lunatic and Manic Fringe inhibit Notch1 activation from Jagged1 and enhance activation from Delta-like 1, Radical Fringe enhances signaling from both. We used a mass spectral approach to determine whether the variable effects of Fringes on Notch1 result from generation of unique glycosylation patterns on Notch1. We found that Lunatic and Manic Fringe modified similar sites on Notch1, while Radical Fringe modified a subset. Fringe modifications at EGF8 and 12 enhanced Notch1 binding to and activation from Delta-like 1, while modifications at EGF6 and 36 (added by Manic and Lunatic but not Radical) inhibited Notch1 activation from Jagged1. Combined, these results suggest that Fringe modifications “mark” different regions in the Notch1 extracellular domain for activation or inhibition. Kakuda and Haltiwanger examine how Fringes regulate Notch1. They show that Radical Fringe modifies a subset of EGF repeats modified by Lunatic and Manic Fringe. Modifications at distinct EGF repeats “mark” the Notch1 extracellular domain, either enhancing or inhibiting activity.