4b04

Crystal structure of the Catalytic Domain of Human DUSP26 (C152S)Crystal structure of the Catalytic Domain of Human DUSP26 (C152S)

Structural highlights

4b04 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.205Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DUS26_HUMAN Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

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 A resolution, respectively. The structure of DUSP26-C showed a novel type of domain-swapped dimer formed by extensive crossover of the C-terminal alpha7 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.

High-resolution crystal structure of the catalytic domain of human dual-specificity phosphatase 26.,Won EY, Xie Y, Takemoto C, Chen L, Liu ZJ, Wang BC, Lee D, Woo EJ, Park SG, Shirouzu M, Yokoyama S, Kim SJ, Chi SW Acta Crystallogr D Biol Crystallogr. 2013 Jun;69(Pt 6):1160-70. doi:, 10.1107/S0907444913004770. Epub 2013 May 16. PMID:23695260^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vasudevan SA, Skoko J, Wang K, Burlingame SM, Patel PN, Lazo JS, Nuchtern JG, Yang J. MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun. 2005 May 6;330(2):511-8. PMID:15796912 doi:10.1016/j.bbrc.2005.03.028
↑ Yu W, Imoto I, Inoue J, Onda M, Emi M, Inazawa J. A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene. 2007 Feb 22;26(8):1178-87. Epub 2006 Aug 21. PMID:16924234 doi:10.1038/sj.onc.1209899
↑ Takagaki K, Shima H, Tanuma N, Nomura M, Satoh T, Watanabe M, Kikuchi K. Characterization of a novel low-molecular-mass dual specificity phosphatase-4 (LDP-4) expressed in brain. Mol Cell Biochem. 2007 Feb;296(1-2):177-84. Epub 2006 Sep 26. PMID:17001450 doi:10.1007/s11010-006-9313-5
↑ Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282
↑ Won EY, Xie Y, Takemoto C, Chen L, Liu ZJ, Wang BC, Lee D, Woo EJ, Park SG, Shirouzu M, Yokoyama S, Kim SJ, Chi SW. High-resolution crystal structure of the catalytic domain of human dual-specificity phosphatase 26. Acta Crystallogr D Biol Crystallogr. 2013 Jun;69(Pt 6):1160-70. doi:, 10.1107/S0907444913004770. Epub 2013 May 16. PMID:23695260 doi:10.1107/S0907444913004770

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Vasudevan SA, Skoko J, Wang K, Burlingame SM, Patel PN, Lazo JS, Nuchtern JG, Yang J. MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun. 2005 May 6;330(2):511-8. PMID:15796912 doi:10.1016/j.bbrc.2005.03.028

[2] Yu W, Imoto I, Inoue J, Onda M, Emi M, Inazawa J. A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene. 2007 Feb 22;26(8):1178-87. Epub 2006 Aug 21. PMID:16924234 doi:10.1038/sj.onc.1209899

[3] Takagaki K, Shima H, Tanuma N, Nomura M, Satoh T, Watanabe M, Kikuchi K. Characterization of a novel low-molecular-mass dual specificity phosphatase-4 (LDP-4) expressed in brain. Mol Cell Biochem. 2007 Feb;296(1-2):177-84. Epub 2006 Sep 26. PMID:17001450 doi:10.1007/s11010-006-9313-5

[4] Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282

[5] Won EY, Xie Y, Takemoto C, Chen L, Liu ZJ, Wang BC, Lee D, Woo EJ, Park SG, Shirouzu M, Yokoyama S, Kim SJ, Chi SW. High-resolution crystal structure of the catalytic domain of human dual-specificity phosphatase 26. Acta Crystallogr D Biol Crystallogr. 2013 Jun;69(Pt 6):1160-70. doi:, 10.1107/S0907444913004770. Epub 2013 May 16. PMID:23695260 doi:10.1107/S0907444913004770

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