Graduate School of Pharmacological Sciences, The University of Tokyo, Japan.
Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Ibaraki, Japan.
FEBS J. 2023 Sep;290(18):4419-4428. doi: 10.1111/febs.16763. Epub 2023 Mar 10.
Over 4 billion years of evolution, multiple mutations, including nucleotide substitutions, gene and genome duplications and recombination, have established de novo genes that translate into proteins with novel properties essential for high-order cellular functions. However, molecular processes through which a protein evolutionarily acquires a novel function are mostly speculative. Recently, we have provided evidence for a potential evolutionary mechanism underlying how, in mammalian cells, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) evolved into a GTP sensor from ATP-utilizing kinase. Mechanistically, PI5P4Kβ has acquired the guanine efficient association (GEA) motif by mutating its nucleotide base recognition sequence, enabling the evolutionary transition from an ATP-dependent kinase to a distinct GTP/ATP dual kinase with its K for GTP falling into physiological GTP concentrations-the genesis of GTP sensing activity. Importantly, the GTP sensing activity of PI5P4Kβ is critical for the manifestation of cellular metabolism and tumourigenic activity in the multicellular organism. The combination of structural, biochemical and biophysical analyses used in our study provides a novel framework for analysing how a protein can evolutionarily acquire a novel activity, which potentially introduces a critical function to the cell.
在 40 多亿年的进化过程中，包括核苷酸替换、基因和基因组重复以及重组在内的多种突变，已经建立了从头基因，这些基因翻译成具有新型特性的蛋白质，对于高级细胞功能至关重要。然而，蛋白质进化获得新功能的分子过程大多是推测性的。最近，我们提供了证据，证明了在哺乳动物细胞中，磷脂酰肌醇 5-磷酸 4-激酶β（PI5P4Kβ）如何从利用 ATP 的激酶进化为 GTP 传感器的潜在进化机制。从机制上讲，PI5P4Kβ通过突变其核苷酸碱基识别序列获得了鸟嘌呤有效结合（GEA）基序，从而使从 ATP 依赖性激酶到具有独特的 GTP/ATP 双重激酶的进化转变成为可能，其对 GTP 的亲和力落入生理 GTP 浓度范围内——这就是 GTP 感应活性的起源。重要的是，PI5P4Kβ 的 GTP 感应活性对于多细胞生物中细胞代谢和致瘤活性的表现至关重要。我们在研究中使用的结构、生化和生物物理分析的结合，为分析蛋白质如何进化获得新的活性提供了一个新的框架，这可能为细胞引入一个关键功能。
