Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation. Issue 10 (11th May 2018)

• Record Type: Journal Article
• Authors: Kim, Kuglae; Cha, Jeong Seok; Cho, Yong-Soon; Kim, Hoyoung; Chang, Nienping; Kim, Hye-Jung; Cho, Hyun-Soo
• Is Part Of: Journal of molecular biology. Volume 430:Issue 10(2018)
• Page Start: 1521
• Page End: 1530
• Publication Date: 2018-05-11
• Subjects: DYRKs dual-specificity tyrosine-regulated kinases -- PRAS40 proline-rich Akt substrate 40 -- NAPA N-terminal auto-phosphorylation accessory -- DH box DYRK homology box -- Tm melting temperature -- PDB Protein Data Bank; crystal structure -- DYRK3 -- PRAS40 -- harmine -- auto-phosphorylation; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.04.001
• Languages: English
• ISSNs: 0022-2836

Abstract

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. Graphical Abstract: Highlights: Structure of DYRK3 unveils three auto-phosphorylation sites. NAPA domain stabilizes N-lobe domain of DYRK3. Phosphorylation sites of PRAS40 by DYRK3 are identified.