Functional molecular evolution of a GTP sensing kinase: PI5P4Kβ
- FEBS J. 2023 Sep;290(18):4419-4428. doi: 10.1111/febs.16763.
- 1. Graduate School of Pharmacological Sciences, The University of Tokyo, Japan.
- 2. Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Ibaraki, Japan.
- 3. Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, OH, USA.
- 4. Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.
- 5. Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
- 6. Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan.
- 7. Department of Cancer Biology, University of Cincinnati College of Medicine, OH, USA.
- 8. Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, Cincinnati, OH, USA.
- 9. Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
- 10. Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Japan.
- 11. Department of Accelerator Science, School of High Energy Accelerator Science, SOKENDAI (The Graduate University for Advanced Studies), Ibaraki, Japan.
- 12. Faculty of Pure and Applied Sciences, University of Tsukuba, Ibaraki, Japan.
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 KM 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.