Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 6 (June 2013)

research papers

Acta Cryst. (2013). D69, 1160-1170    [ doi:10.1107/S0907444913004770 ]

High-resolution crystal structure of the catalytic domain of human dual-specificity phosphatase 26

E.-Y. Won, Y. Xie, C. Takemoto, L. Chen, Z.-J. Liu, B.-C. Wang, D. Lee, E.-J. Woo, S. G. Park, M. Shirouzu, S. Yokoyama, S. J. Kim and S.-W. Chi

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 [alpha]7 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.

PDB references: 2e0t and 4b04

Keywords: PTP; DUSP26; catalytic domain; domain swapping.

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[ doi:10.1107/S0907444913004770/mh5076sup1.pdf ]
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