School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia.
Sci Signal. 2019 Jan 22;12(565):eaau8645. doi: 10.1126/scisignal.aau8645.
Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Phosphoproteomics has improved the understanding of the function of even the most well-characterized protein kinases by revealing new downstream substrates and biology. However, current biochemical and bioinformatic approaches have only identified kinases for less than 5% of the phosphoproteome, and functional assignments of phosphosites are almost negligible. Notably, our understanding of the relationship between kinases and their substrates follows a power law distribution, with almost 90% of phosphorylation sites currently assigned to the top 20% of kinases. In addition, more than 150 kinases do not have a single known substrate. Despite a small group of kinases dominating biomedical research, the number of substrates assigned to a kinase does not correlate with disease relevance as determined by pathogenic human mutation prevalence and mouse model phenotypes. Improving our understanding of the substrates targeted by all kinases and functionally annotating the phosphoproteome will be broadly beneficial. Advances in phosphoproteomics technologies, combined with functional screening approaches, should make it feasible to illuminate the connectivity and functionality of the entire phosphoproteome, providing enormous opportunities for discovering new biology, therapeutic targets, and possibly diagnostics.
蛋白质磷酸化是蛋白质功能和生物结果的主要调节剂。这首先是通过功能生化实验认识到的，在过去十年中，质谱技术的重大技术进步使在全球范围内研究蛋白质磷酸化成为可能。这个快速发展的磷酸蛋白质组学领域揭示了超过 100,000 种不同的磷酸化事件发生在人类细胞中，这可能影响到每一种蛋白质的功能。磷酸蛋白质组学通过揭示新的下游底物和生物学信息，提高了对即使是研究最透彻的蛋白激酶功能的理解。然而，目前的生化和生物信息学方法仅鉴定了磷酸蛋白质组中不到 5%的激酶，并且磷酸化位点的功能分配几乎可以忽略不计。值得注意的是，我们对激酶与其底物之间关系的理解遵循幂律分布，目前近 90%的磷酸化位点被分配给前 20%的激酶。此外，超过 150 种激酶没有一个已知的底物。尽管一小部分激酶主导着生物医学研究，但分配给激酶的底物数量与疾病相关性无关，这是由致病性人类突变流行率和小鼠模型表型决定的。更好地理解所有激酶的靶底物并对磷酸蛋白质组进行功能注释将具有广泛的益处。磷酸蛋白质组学技术的进步，结合功能筛选方法，应该可以阐明整个磷酸蛋白质组的连接性和功能，为发现新的生物学、治疗靶点，甚至可能是诊断方法提供巨大的机会。
