Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation

Kuglae Kim; Jeong Seok Cha; Yong Soon Cho; Hoyoung Kim; Nienping Chang; Hye Jung Kim; Hyun Soo Cho

doi:10.1016/j.jmb.2018.04.001

Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation

Kuglae Kim, Jeong Seok Cha, Yong Soon Cho, Hoyoung Kim, Nienping Chang, Hye Jung Kim, Hyun Soo Cho

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.

Original language	English
Pages (from-to)	1521-1530
Number of pages	10
Journal	Journal of Molecular Biology
Volume	430
Issue number	10
DOIs	https://doi.org/10.1016/j.jmb.2018.04.001
Publication status	Published - 2018 May 11

Bibliographical note

Funding Information:
We thank the staff scientists of Pohang Light Source (South Korea) for assistance with the beamlines (5C and 7A) and of Photon Factory (Japan) beamlines (1A and 17A). We thank Soo Young Choi from Hallym University, who provided the PRAS40 gene. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2016R1A2B2013305, 2016R1A5A1010764, 2017M3A9F6029755) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (Grant No. 916006-2).

Funding Information:
We thank the staff scientists of Pohang Light Source (South Korea) for assistance with the beamlines (5C and 7A) and of Photon Factory (Japan) beamlines (1A and 17A). We thank Soo Young Choi from Hallym University , who provided the PRAS40 gene. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT ( NRF-2016R1A2B2013305 , 2016R1A5A1010764 , 2017M3A9F6029755 ) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (Grant No. 916006-2 ).

Publisher Copyright:
© 2018 Elsevier Ltd

All Science Journal Classification (ASJC) codes

Structural Biology
Molecular Biology

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10.1016/j.jmb.2018.04.001

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title = "Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation",

abstract = "Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.",

author = "Kuglae Kim and Cha, {Jeong Seok} and Cho, {Yong Soon} and Hoyoung Kim and Nienping Chang and Kim, {Hye Jung} and Cho, {Hyun Soo}",

note = "Funding Information: We thank the staff scientists of Pohang Light Source (South Korea) for assistance with the beamlines (5C and 7A) and of Photon Factory (Japan) beamlines (1A and 17A). We thank Soo Young Choi from Hallym University, who provided the PRAS40 gene. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2016R1A2B2013305, 2016R1A5A1010764, 2017M3A9F6029755) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (Grant No. 916006-2). Funding Information: We thank the staff scientists of Pohang Light Source (South Korea) for assistance with the beamlines (5C and 7A) and of Photon Factory (Japan) beamlines (1A and 17A). We thank Soo Young Choi from Hallym University , who provided the PRAS40 gene. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT ( NRF-2016R1A2B2013305 , 2016R1A5A1010764 , 2017M3A9F6029755 ) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (Grant No. 916006-2 ). Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

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AU - Kim, Kuglae

AU - Cha, Jeong Seok

AU - Cho, Yong Soon

AU - Kim, Hoyoung

AU - Chang, Nienping

AU - Kim, Hye Jung

AU - Cho, Hyun Soo

N1 - Funding Information: We thank the staff scientists of Pohang Light Source (South Korea) for assistance with the beamlines (5C and 7A) and of Photon Factory (Japan) beamlines (1A and 17A). We thank Soo Young Choi from Hallym University, who provided the PRAS40 gene. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2016R1A2B2013305, 2016R1A5A1010764, 2017M3A9F6029755) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (Grant No. 916006-2). Funding Information: We thank the staff scientists of Pohang Light Source (South Korea) for assistance with the beamlines (5C and 7A) and of Photon Factory (Japan) beamlines (1A and 17A). We thank Soo Young Choi from Hallym University , who provided the PRAS40 gene. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT ( NRF-2016R1A2B2013305 , 2016R1A5A1010764 , 2017M3A9F6029755 ) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by Ministry of Agriculture, Food and Rural Affairs (Grant No. 916006-2 ). Publisher Copyright: © 2018 Elsevier Ltd

PY - 2018/5/11

Y1 - 2018/5/11

N2 - Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.

AB - Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.

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Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation

Abstract

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