Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2215431120. doi: 10.1073/pnas.2215431120. Epub 2023 May 30.
Defining all sites for a post-translational modification in the cell, and identifying their upstream modifying enzymes, is essential for a complete understanding of a modification's function. However, the complete mapping of a modification in the proteome and definition of its associated enzyme-substrate network is rarely achieved. Here, we present the protein methylation network for Through a formal process of defining and quantifying all potential sources of incompleteness, for both the methylation sites in the proteome and also protein methyltransferases, we prove that this protein methylation network is now near-complete. It contains 33 methylated proteins and 28 methyltransferases, comprising 44 enzyme-substrate relationships, and a predicted further three enzymes. While the precise molecular function of most methylation sites is unknown, and it remains possible that other sites and enzymes remain undiscovered, the completeness of this protein modification network is unprecedented and allows us to holistically explore the role and evolution of protein methylation in the eukaryotic cell. We show that while no single protein methylation event is essential in yeast, the vast majority of methylated proteins are themselves essential, being primarily involved in the core cellular processes of transcription, RNA processing, and translation. This suggests that protein methylation in lower eukaryotes exists to fine-tune proteins whose sequences are evolutionarily constrained, providing an improvement in the efficiency of their cognate processes. The approach described here, for the construction and evaluation of post-translational modification networks and their constituent enzymes and substrates, defines a formal process of utility for other post-translational modifications.
确定细胞中所有翻译后修饰的位点，并鉴定其上游修饰酶，对于全面了解修饰的功能至关重要。然而，很少能完全绘制修饰在蛋白质组中的图谱并定义其相关的酶-底物网络。在这里，我们呈现了蛋白质甲基化网络。通过正式定义和量化蛋白质组中甲基化位点和蛋白质甲基转移酶的所有潜在不完整来源的过程，我们证明了这个蛋白质甲基化网络现在几乎是完整的。它包含 33 个甲基化蛋白和 28 个甲基转移酶，包括 44 个酶-底物关系，并预测了另外三个酶。虽然大多数甲基化位点的精确分子功能未知，并且可能仍然存在未发现的其他位点和酶，但这个蛋白质修饰网络的完整性是前所未有的，使我们能够全面探索蛋白质甲基化在真核细胞中的作用和进化。我们表明，虽然在酵母中没有单个蛋白质甲基化事件是必需的，但绝大多数甲基化蛋白本身是必需的，主要参与转录、RNA 处理和翻译等核心细胞过程。这表明在低等真核生物中，蛋白质甲基化的存在是为了微调其序列受到进化限制的蛋白质，从而提高其同源过程的效率。这里描述的用于构建和评估翻译后修饰网络及其组成酶和底物的方法，为其他翻译后修饰定义了一个正式的有用过程。
