Cytosolic O-glycosylation is abundant in nerve terminals
Cytosolic O-glycosylation is abundant in nerve terminals
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DOI：
10.1046/j.1471-4159.2001.00655.x
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发表时间：
2001-12-01
影响因子：
4.7
通讯作者：
Hart, GW
中科院分区：
文献类型：
--
作者：
Cole, RN;Hart, GW
磷酸化在调节生长激素迁移和蛋白质在神经末梢的运输中起着关键作用。在这里，我们发现神经末梢蛋白含有另一个丰富的翻译后修饰：与丝氨酸或苏氨酸的羟基相连的β-N-乙酰氨基葡萄糖(O-GlcNAc(1))。O-GlcNAc修饰对胚胎发育是必不可少的，越来越多的证据表明O-GlcNAc是一种调节修饰，影响许多磷酸化蛋白。我们发现，调节O-GlcNAc修饰的两种酶--O-GlcNAc转移酶(OGT)和N-乙酰-β-D-氨基葡萄糖苷酶(O-GlcNAcase)的活性和表达存在于神经末梢结构(突触体)中，尤其是在突触体的胞浆中。许多突触体蛋白都被O-GlcNAc高度修饰。虽然这些蛋白大多以低丰度存在，但我们通过蛋白质组学分析鉴定了三种神经元特异性的O-GlcNAc修饰蛋白：崩塌反应介质蛋白-2(CRMP-2)、泛素羧基水解酶-L1(UCH-L1)和β-突触核蛋白。CRMP-2是突触体内一种主要的O-GlcNAc修饰蛋白，与生长锥塌陷有关。所有这三种蛋白质都与调节细胞内信号或神经退行性疾病的级联反应有关。我们认为神经末梢的O-GlcNAc修饰有助于调节这些和其他突触体蛋白的功能，O-GlcNAc可能在神经退行性疾病中发挥作用。
Phosphorylation plays a key role in regulating growth cone migration and protein trafficking in nerve terminals. Here we show that nerve terminal proteins contain another abundant post-translational modification: beta -N-acetylglucosamine linked to hydroxyls of serines or threonines (O-GlcNAc(1)). O-GlcNAc modifications are essential for embryogenesis and mounting evidence suggests that O-GlcNAc is a regulatory modification that affects many phosphorylated proteins. We show that the activity and expression of O-GlcNAc transferase (OGT) and N-acetyl-beta -D-glucosaminidase (O-GlcNAcase), the two enzymes regulating O-GlcNAc modifications, are present in nerve terminal structures (synaptosomes) and are particularily abundant in the cytosol of synaptosomes. Numerous synaptosome proteins are highly modified with O-GlcNAc. Although most of these proteins are present in low abundance, we identified by proteomic analysis three neuron-specific O-GlcNAc modified proteins: collapsin response mediator protein-2 (CRMP-2), ubiquitin carboxyl hydrolase-L1 (UCH-L1) and beta -synuclein. CRMP-2, which is involved in growth cone collapse, is a major O-GlcNAc modified protein in synaptosomes. All three proteins are implicated in regulatory cascades that mediate intracellular signaling or neurodegenerative diseases. We propose that O-GlcNAc modifications in the nerve terminal help regulate the functions of these and other synaptosome proteins, and that O-GlcNAc may play a role in neurodegenerative disease.