Atsuo Sasaki (Associate Professor, Univ. of Cincinnati; Project Professor, Keio Univ.), one of the leaders of the GTP group, while studying the RAS of G-proteins, became very curious that the behavior of GTP fluctuations was different from that of ATP. Why is there such a wide range in GTP concentration? He could not find it in textbooks, nor could he find it in papers. He asked a prominent researcher at Harvard University, but could not get an answer.
There is something important that has been overlooked. For example, could there be a mechanism to detect GTP concentration or an unknown GTP control system? If there is a GTP sensor, it should bind to GTP. If there is a GTP sensor, it should bind to GTP, so let's try to identify the molecule that binds to GTP. This was the first step that led to my current GTP research.
Figure Using GTP-immobilized beads, the protein that binds to GTP was searched for in the cell, and PI5P4Kβ was discovered.
Among the GTP-binding molecules that Sasaki fished out was the inositol lipid kinase PI5P4Kβ, which had been shown to be important in metabolism and cancer from analysis of knockout mice. But why would a kinase that is supposed to prefer ATP bind to GTP? What is the physiological significance of using GTP and how is it linked to disease? These were important questions, but Sasaki ran into a wall.
In order to advance GTP biology, it is necessary to understand the GTP recognition mechanism at the atomic level. The development of GTP-binding mutants and inhibitors based on structural information will enable us to analyze the role of GTP in cells and individuals and the evolution of GTP recognition.
As fate would have it, we met up with Tsune Takeuchi (Professor, The University of Tokyo), an expert in NMR and drug discovery science, and Toshiya Senda (Professor, KEK), a leader in structural analysis using X-ray and cryo-electron microscopy, to form GTP-GEEKS, a geeky GTP research team with Sasaki, Takeuchi, and Senda at its core. Since its birth in 2011, GTP-GEEKS has brought together various experts in physiological and multilayered omics, synthetic biology, computational science, evolutionary biology, nano-quantitative biology, etc., under the slogan "science that transcends disciplinary boundaries. We also hold GTP workshops at home and abroad, and are the one and only research group with a geek focus on GTP. GTP-GEEKS is a research group where experts in various fields are united in the spirit of harmony and circle. That is GTP-GEEKS. Our research has revealed that there are signals generated by fluctuations in GTP concentration, and that these signals are used to generate robustness of life and the acquisition of new functions of life associated with evolution. We are developing integrative GTP biology to elucidate these signals and to apply them to medicine and industry.
From left: Professor Toshiya Senda, Professor Koh Takeuchi, and Assistant Professor Miki Senda. At the photon factory