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Activity-specificity trade-off gives PI5P4Kβ a nucleotide preference to function as a GTP-sensing kinase.

Takeuchi, K.; Ikeda, Y.; Senda, M.; Harada, A.; Okuwaki, K.; Fukuzawa, K.; Nakagawa, S.; Yu, H.; Nagase, L.; Imai, M.; Sasaki, M.; Lo, Y.; Sasaki, A. T.; Senda, T.

2020-06-10 biochemistry
10.1101/2020.06.09.137430 bioRxiv
Show abstract

Most kinases function with ATP. However, contrary to the prevailing dogma, phosphatidylinositol 5-phosphate 4-kinase {beta} (PI5P4K{beta}) utilizes GTP as a primary phosphate donor with a unique binding mode for GTP. Although PI5P4K{beta} is evolved from a primordial ATP-utilizing enzyme, PI4P5K, how PI5P4K{beta} evolutionarily acquired the GTP preference to function as a cellular GTP sensor remains unclear. In this study, we show that the short nucleotide base-recognition motif, TRNVF, is responsible for the GTP binding of PI5P4K{beta}, and also confers onto PI5P4K{beta} an unexpected specificity that extends to inosine triphosphate (ITP) and xanthosine triphosphate (XTP). A mutational study with GTP analogues suggests that the extended specificity is an obligatory consequence to the acquisition of GTP-dependent activity. However, as the cellular concentrations of ITP and XTP are typically negligible, PI5P4K{beta} can still function as a GTP sensor, suggesting that the cellular physiological conditions leave room for the functional evolution of PI5P4K{beta}.

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