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.authorWon, Eun-Youngko
dc.contributor.authorLee, Sang-Okko
dc.contributor.authorLee, Dong-Hwako
dc.contributor.authorLee, Daeyoupko
dc.contributor.authorBae, Kwang-Heeko
dc.contributor.authorLee, Sang Chulko
dc.contributor.authorKim, Seung Junko
dc.contributor.authorChi, Seung-Wookko
dc.date.accessioned2016-11-09T06:28:00Z-
dc.date.available2016-11-09T06:28:00Z-
dc.date.created2016-10-27-
dc.date.created2016-10-27-
dc.date.issued2016-09-
dc.identifier.citationPLOS ONE, v.11, no.9, pp.e0162115-
dc.identifier.issn1932-6203-
dc.identifier.urihttp://hdl.handle.net/10203/213873-
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 angstrom 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 alpha 8-helix and has an additional alpha 1-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 alpha 7-alpha 8 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 structure-based rational design of novel DUSP26-targeting anticancer therapeutics-
dc.languageEnglish-
dc.publisherPUBLIC LIBRARY SCIENCE-
dc.subjectCHROMOSOME ARM 8P-
dc.subjectCRYSTAL-STRUCTURE-
dc.subjectPROTEIN PHOSPHATASE-
dc.subjectP53 RESTORATION-
dc.subjectCELL-GROWTH-
dc.subjectDUSP26-
dc.subjectNEUROBLASTOMA-
dc.subjectSUPPRESSION-
dc.subjectACTIVATION-
dc.subjectRESOLUTION-
dc.titleStructural Insight into the Critical Role of the N-Terminal Region in the Catalytic Activity of Dual-Specificity Phosphatase 26-
dc.typeArticle-
dc.identifier.wosid000382855600107-
dc.identifier.scopusid2-s2.0-84990902023-
dc.type.rimsART-
dc.citation.volume11-
dc.citation.issue9-
dc.citation.beginningpagee0162115-
dc.citation.publicationnamePLOS ONE-
dc.identifier.doi10.1371/journal.pone.0162115-
dc.contributor.localauthorLee, Daeyoup-
dc.contributor.nonIdAuthorLee, Sang-Ok-
dc.contributor.nonIdAuthorLee, Dong-Hwa-
dc.contributor.nonIdAuthorBae, Kwang-Hee-
dc.contributor.nonIdAuthorLee, Sang Chul-
dc.contributor.nonIdAuthorKim, Seung Jun-
dc.contributor.nonIdAuthorChi, Seung-Wook-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordPlusCHROMOSOME ARM 8P-
dc.subject.keywordPlusCRYSTAL-STRUCTURE-
dc.subject.keywordPlusPROTEIN PHOSPHATASE-
dc.subject.keywordPlusP53 RESTORATION-
dc.subject.keywordPlusCELL-GROWTH-
dc.subject.keywordPlusDUSP26-
dc.subject.keywordPlusNEUROBLASTOMA-
dc.subject.keywordPlusSUPPRESSION-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusRESOLUTION-
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