Structural insight into the critical role of the N-terminal region in the catalytic activity of dual-specificity phosphatase 26

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dc.contributor.authorEun Young Won-
dc.contributor.authorSang-Ok Lee-
dc.contributor.authorDong-Hwa Lee-
dc.contributor.authorD Lee-
dc.contributor.authorKwang-Hee Bae-
dc.contributor.authorSang Chul Lee-
dc.contributor.authorSeung Jun Kim-
dc.contributor.authorSeung-Wook Chi-
dc.description.abstractHuman dual-specificity phosphatase 26 (DUSP26) is a novel target for anticancer therapy because its dephosphorylation of the p53 tumor suppressor regulates the apoptosis of cancer cells. DUSP26 inhibition results in neuroblastoma cell cytotoxicity through p53-mediated apoptosis. Despite the previous structural studies of DUSP26 catalytic domain (residues 61-211, DUSP26-C), the high-resolution structure of its catalytically active form has not been resolved. In this study, we determined the crystal structure of a catalytically active form of DUSP26 (residues 39-211, DUSP26-N) with an additional N-terminal region at 2.0 A resolution. Unlike the C-terminal domain-swapped dimeric structure of DUSP26-C, the DUSP26-N (C152S) monomer adopts a fold-back conformation of the C-terminal a8-helix and has an additional a1-helix in the N-terminal region. Consistent with the canonically active conformation of its protein tyrosine phosphate-binding loop (PTP loop) observed in the structure, the phosphatase assay results demonstrated that DUSP26-N has significantly higher catalytic activity than DUSP26-C. Furthermore, size exclusion chromatography-multiangle laser scattering (SEC-MALS) measurements showed that DUSP26-N (C152S) exists as a monomer in solution. Notably, the crystal structure of DUSP26-N (C152S) revealed that the N-terminal region of DUSP26-N (C152S) serves a scaffolding role by positioning the surrounding a7-a8 loop for interaction with the PTP-loop through formation of an extensive hydrogen bond network, which seems to be critical in making the PTP-loop conformation competent for phosphatase activity. Our study provides the first high-resolution structure of a catalytically active form of DUSP26, which will contribute to the structurebased rational design of novel DUSP26-targeting anticancer therapeutics.-
dc.publisherPublic Library of Science-
dc.titleStructural insight into the critical role of the N-terminal region in the catalytic activity of dual-specificity phosphatase 26-
dc.title.alternativeStructural insight into the critical role of the N-terminal region in the catalytic activity of dual-specificity phosphatase 26-
dc.citation.titlePLoS One-
dc.contributor.affiliatedAuthorEun Young Won-
dc.contributor.affiliatedAuthorSang-Ok Lee-
dc.contributor.affiliatedAuthorDong-Hwa Lee-
dc.contributor.affiliatedAuthorKwang-Hee Bae-
dc.contributor.affiliatedAuthorSang Chul Lee-
dc.contributor.affiliatedAuthorSeung Jun Kim-
dc.contributor.affiliatedAuthorSeung-Wook Chi-
dc.identifier.bibliographicCitationPLoS One, vol. 11, no. 9, pp. e0162115-e0162115-
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
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