The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity.
The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity.
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DOI：
10.1016/j.str.2022.04.004
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发表时间：
2022-06-02
期刊：
影响因子：
5.7
通讯作者：
Senda, Toshiya
中科院分区：
文献类型：
--
作者：
Takeuchi, Koh;Ikeda, Yoshiki;Senda, Miki;Harada, Ayaka;Okuwaki, Koji;Fukuzawa, Kaori;Nakagawa, So;Yu, Hong Yang;Nagase, Lisa;Imai, Misaki;Sasaki, Mika;Lo, Yu-Hua;Ito, Doshun;Osaka, Natsuki;Fujii, Yuki;Sasaki, Atsuo T.;Senda, Toshiya
与大多数激酶不同，磷脂酰肌醇5-磷酸4-激酶β（PI 5 P4 K β）利用GTP作为生理磷酸供体并调节应激下的细胞生长（即，GTP依赖的压力恢复力）。然而，其GTP反应性的起源和演变仍然未知。在此，我们发现PI 5 P4 K β通过产生短的双核苷酸识别基序GEA（Guanine Efficient-Association）获得了GTP偏好性。比较660种激酶和128种G蛋白的核碱基识别发现，大多数激酶和PI 5 P4 K β使用其主链原子识别腺嘌呤，而侧链原子则需要鸟嘌呤识别。GEA基序的突变分析显示，GTP反应性的获得伴随着对ITP和XTP的扩展活性。沿着进化分析数据指出GEA基序的强负选择，这些结果表明PI 5 P4 K β的GTP-反应性是通过活性和特异性之间的折衷而进化的，这支持了GTP依赖性应激恢复力的发展。PI 5 P4 K β是一种独特的利用GTP的激酶，作为细胞内GTP传感器发挥作用。Takeuchi等人表明，GTP结合需要GTP/ATP双重识别基序（称为GEA），该基序出现在脊椎动物中。进一步的分析表明，GEA基序中的有限取代将PI 5 P4 K β转化为不寻常的GTP利用激酶。
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 via generating a short dual nucleotide-recognizing motif, GEA (Guanine Efficient-Association). Comparison of nucleobase recognition with 660 kinases and 128 G-proteins has uncovered that most kinases and PI5P4Kβ use their mainchain atoms for adenine recognition, while the sidechain atoms are required for guanine recognition. Mutational analysis of the GEA motif revealed that the acquisition of the GTP-reactivity is accompanied by an extended activity to ITP and XTP. Along with the evolutionary analysis data that points strong negative selection of the GEA motif, these results suggest that the GTP-responsiveness of PI5P4Kβ is evolved by a compromised trade-off between activity and specificity, underpinning the development of the GTP-dependent stress resilience. PI5P4Kβ is a unique GTP-utilizing kinase that functions as an intracellular GTP sensor. Takeuchi et al. show that GTP binding requires the GTP/ATP dual recognition motif, named GEA, which emerged in a vertebrate. Further analyses reveal that limited substitutions in the GEA motif turned PI5P4Kβ into an unusual GTP-utilizing kinase.
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