@article{cbd287351ad642a9b728694f34b65e5e,
title = "The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity",
abstract = "Unlike most kinases, phosphatidylinositol 5-phosphate 4-kinase β (PI5P4Kβ) utilizes GTP as a physiological phosphate donor and regulates cell growth under stress (i.e., GTP-dependent stress resilience). However, the genesis and evolution of its GTP responsiveness remain unknown. Here, we reveal that PI5P4Kβ has acquired GTP preference by generating a short dual-nucleotide-recognizing motif called the guanine efficient association (GEA) motif. Comparison of nucleobase recognition with 660 kinases and 128 G proteins has uncovered that most kinases and PI5P4Kβ use their main-chain atoms for adenine recognition, while the side-chain atoms are required for guanine recognition. Mutational analysis of the GEA motif revealed that the acquisition of GTP reactivity is accompanied by an extended activity toward inosine triphosphate (ITP) and xanthosine triphosphate (XTP). Along with the evolutionary analysis data that point to strong negative selection of the GEA motif, these results suggest that the GTP responsiveness of PI5P4Kβ has evolved from a compromised trade-off between activity and specificity, underpinning the development of the GTP-dependent stress resilience.",
keywords = "GTP, GTP sensor, PI5P4K, activity, evolution, kinase, specificity, stress resilience",
author = "Koh Takeuchi and Yoshiki Ikeda and Miki Senda and Ayaka Harada and Koji Okuwaki and Kaori Fukuzawa and So Nakagawa and Yu, {Hong Yang} and Lisa Nagase and Misaki Imai and Mika Sasaki and Lo, {Yu Hua} and Doshun Ito and Natsuki Osaka and Yuki Fujii and Sasaki, {Atsuo T.} and Toshiya Senda",
note = "Funding Information: We thank Dr. Tomomi Sato for her contribution to the early stage of this work. We thank Dr. Yoshihisa Hirota, Ms. Emily Dobbs and Dr. Eric P. Smith for their excellent proofreading. This work was supported in part by a UC College of Medicine Research Innovation grant, a Marlene Harris Ride Cincinnati grant, JSPS KAKENHI ( 20H03165 ), and NIH grants ( R21NS100077 , R01NS089815 , and R01CA255331 ) to A.T.S. Support was also provided by the Project for Cancer Research and Therapeutic Evolution (P-CREATE; JP20cm0106173 to A.T.S., T.S., and K.T.) from the Japan Agency for Medical Research and Development ( AMED ), Generating research infrastructure and novel technologies for anti-infective drug and vaccine discovery from AMED ( 21gm1610003h0201 to K.T.), the Plat-form Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED under grant nos. JP19a.m.0101071 (T.S.) and JP19a.m.0101113 (K.F.) (support nos. 0586 and 2194 ), JST , CREST grant JP20356709 , Japan, and Swiss Light Source (proposals 20191094 and 20191134). The work was also supported in part by KAKENHI (grants 20H03378 and 20H04722 to K.T.) from the Japan Society for the Promotion of Science (JSPS). This work was supported by the public accession beam time of the Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (accession nos. 2017G147 , 2019G063 , and 2021G054 ). Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = jun,
day = "2",
doi = "10.1016/j.str.2022.04.004",
language = "English",
volume = "30",
pages = "886--899.e4",
journal = "Structure with Folding & design",
issn = "0969-2126",
publisher = "Cell Press",
number = "6",
}