title: High-resolution crystal structure of the catalytic domain of human dual-specificity phosphatase 26.
abstract: Dual-specificity phosphatases (DUSPs) play an important role in regulating cellular signalling pathways governing cell growth, differentiation and apoptosis. Human DUSP26 inhibits the apoptosis of cancer cells by dephosphorylating substrates such as p38 and p53. High-resolution crystal structures of the DUSP26 catalytic domain (DUSP26-C) and its C152S mutant [DUSP26-C (C152S)] have been determined at 1.67 and 2.20 Å resolution, respectively. The structure of DUSP26-C showed a novel type of domain-swapped dimer formed by extensive crossover of the C-terminal α7 helix. Taken together with the results of a phosphatase-activity assay, structural comparison with other DUSPs revealed that DUSP26-C adopts a catalytically inactive conformation of the protein tyrosine phosphate-binding loop which significantly deviates from that of canonical DUSP structures. In particular, a noticeable difference exists between DUSP26-C and the active forms of other DUSPs at the hinge region of a swapped C-terminal domain. Additionally, two significant gaps were identified between the catalytic core and its surrounding loops in DUSP26-C, which can be exploited as additional binding sites for allosteric enzyme regulation. The high-resolution structure of DUSP26-C may thus provide structural insights into the rational design of DUSP26-targeted anticancer drugs.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Won
authors.forename: Yong
authors.initials: Y
authors.lastname: Xie
authors.forename: Chie
authors.initials: C
authors.lastname: Takemoto
authors.forename: Lirong
authors.initials: L
authors.lastname: Chen
authors.forename: Zhi Jie
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Bi Cheng
authors.initials: BC
authors.lastname: Wang
authors.forename: Daeyoup
authors.initials: D
authors.lastname: Lee
authors.forename: Eui Jeon
authors.initials: EJ
authors.lastname: Woo
authors.forename: Sung Goo
authors.initials: SG
authors.lastname: Park
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Chi
mesh_terms: D002151:Calorimetry; D020134:Catalytic Domain; D054637:Dual-Specificity Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D050505:Mutant Proteins; D054639:Mitogen-Activated Protein Kinase Phosphatases; C500883:DUSP26 protein, human; D054637:Dual-Specificity Phosphatases
keywords: DUSP26; PTP; catalytic domain; domain swapping