Activation pathway of Hippo/SIK1 protein kinase in Arabidopsis

Recently, the research group of Xu Qin and Gong Qingqiu from the School of Life Science and Technology of Shanghai Jiao Tong University jointly published a research paper entitled An Allosteric Regulation Mechanism of Arabidopsis Serine/Threonine Kinase 1 (SIK1) Through Phosphorylation in Computational and Structural Biotechnology Journal
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Mu Junxi, a 2018 undergraduate student of the School of Life Science and Technology, and Zhou Jiali, a 2020 graduate student, are the co-first authors of this article.

This work continues the functional study of the plant Hippo/STE20 isofunctional protein SIK1 by Gong Qingqiu's group, and reveals the dynamic conformational changes and residue action paths of the SIK1 kinase domain during phosphorylation and activation from a microscopic perspective
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By comparing the one-dimensional sequences and three-dimensional structures of various serine/threonine kinases, the stable conformations of the SIK1 kinase domain in phosphorylation-activated and dephosphorylation-inactive states were constructed using homology modeling; The conformational change process after inactive phosphorylation and active dephosphorylation, based on the residue movement correlation, revealed the residue action pathway of phosphorylation site regulating the opening and closing of the active pocket through allosteric effect; the activation pathway was verified experimentally The importance of several key residues in kinase activity

Figure 1.
Allosteric effects of phosphorylation regulate the opening and closing of the active pocket

Although the N-terminal and C-terminal sequences of SIK1 are both plant-specific and highly disordered, its kinase domain has high structural homology to human MST1/2 and other STE20 family protein kinases, and its activation mechanism is highly similar
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The sequence conservation of key amino acids in the activation pathways of these kinases is related to the flexibility of their sites: that is, the low-flexibility region of the core is highly conserved similar to the catalytic site residues, while the phosphorylation sites and active regulatory sites at both ends of the pathway are located in high The flexible loop region instead allows relatively different residues to perform similar functions

Figure 2.
The mechanism of action of key residues revealed by the combination of computation and experiments

Since 2015, the core kinase SIK1 of the plant Hippo pathway was reported for the first time in the world, the SIK1-MOB1 module was established, and the functions of Hippo/STE20 in promoting cell division exit and polarity establishment were extended to the eukaryotic domain.
Gong Qingqiu’s project The group continues to identify the upstream and downstream components of the plant Hippo pathway, and conduct evolutionary biological studies of the pathway
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This research was supported by the National Natural Science Foundation of China, the Shanghai Jiaotong University Interdisciplinary Program of Medicine and Engineering, and the Interdisciplinary Research Program of the Life Science Discipline Group

Paper link : https://doi.

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School of Life Science and Technology

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School of Life Science and Technology