Deciphering the Functions of O-GlcNAc Glycosylation in the Brain: The Role of Site-Specific Quantitative O-GlcNAcomics,Biochemistry

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Deciphering the Functions of O-GlcNAc Glycosylation in the Brain: The Role of Site-Specific Quantitative O-GlcNAcomics
Biochemistry ( IF 2.9 ) Pub Date : 2018-06-23 00:00:00 , DOI: 10.1021/acs.biochem.8b00516
John W. Thompson ₁ , Alexander W. Sorum ₁ , Linda C. Hsieh-Wilson ₁

Affiliation

The dynamic posttranslational modification O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) is present on thousands of intracellular proteins in the brain. Like phosphorylation, O-GlcNAcylation is inducible and plays important functional roles in both physiology and disease. Recent advances in mass spectrometry (MS) and bioconjugation methods are now enabling the mapping of O-GlcNAcylation events to individual sites in proteins. However, our understanding of which glycosylation events are necessary for regulating protein function and controlling specific processes, phenotypes, or diseases remains in its infancy. Given the sheer number of O-GlcNAc sites, methods for identifying promising sites and prioritizing them for time- and resource-intensive functional studies are greatly needed. Revealing sites that are dynamically altered by different stimuli or disease states will likely go a long way in this regard. Here, we describe advanced methods for identifying O-GlcNAc sites on individual proteins and across the proteome and for determining their stoichiometry in vivo. We also highlight emerging technologies for quantitative, site-specific MS-based O-GlcNAc proteomics (O-GlcNAcomics), which allow proteome-wide tracking of O-GlcNAcylation dynamics at individual sites. These cutting-edge technologies are beginning to bridge the gap between the high-throughput cataloguing of O-GlcNAcylated proteins and the relatively low-throughput study of individual proteins. By uncovering the O-GlcNAcylation events that change in specific physiological and disease contexts, these new approaches are providing key insights into the regulatory functions of O-GlcNAc in the brain, including their roles in neuroprotection, neuronal signaling, learning and memory, and neurodegenerative diseases.

中文翻译：

解密O-GlcNAc糖基化在大脑中的功能：特定于站点的定量O-GlcNAcomics的作用

动态翻译后修饰O-连接的β- N-乙酰氨基葡糖糖基化（O-GlcNAcylation）存在于大脑中成千上万种细胞内蛋白质上。像磷酸化一样，O-GlcNAcylation是可诱导的，并且在生理和疾病中都起着重要的功能作用。质谱（MS）和生物共轭方法的最新进展现在使O-GlcNAcylation事件映射到蛋白质中的单个位点成为可能。但是，我们对哪些糖基化事件对于调节蛋白质功能和控制特定过程，表型或疾病所必需的了解仍处于起步阶段。鉴于O-GlcNAc站点的数量众多，非常需要用于确定有前途的站点并对其进行优先排序的方法，以进行时间和资源密集的功能研究。在这方面，由不同的刺激或疾病状态动态改变的显露位点可能会走很长一段路。在这里，我们描述了用于识别单个蛋白质和整个蛋白质组上的O-GlcNAc位点并确定其体内化学计量的先进方法。我们还将重点介绍针对基于位点的定量定量O-GlcNAc蛋白质组学（O-GlcNAcomics）的新兴技术，这些技术可以在整个蛋白质组范围内跟踪各个位点的O-GlcNAcylation动力学。这些尖端技术开始弥合O-GlcNAcylated蛋白的高通量分类与单个蛋白的相对低通量研究之间的差距。通过发现在特定生理和疾病环境中发生变化的O-GlcNAcylation事件，

更新日期：2018-06-23

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