4HRF: Atomic Structure Of Dusp26

Citation:
Abstract
Regulation of p53 phosphorylation is critical to control its stability and biological activity. Dual-specificity phosphatase 26 (DUSP26) is a brain phosphatase highly overexpressed in neuroblastoma, which has been implicated in dephosphorylating phospho-Ser20 and phospho-Ser37 in the p53 transactivation domain. In this paper, we report the 1.68 A crystal structure of a catalytically inactive mutant (Cys152Ser) of DUSP26 lacking the first 60 N-terminal residues (DeltaN60-C/S-DUSP26). This structure reveals the architecture of a dual-specificity phosphatase domain related in structure to Vaccinia virus VH1. DUSP26 adopts a closed conformation of the protein tyrosine phosphatase (PTP)-binding loop, which results in an unusually shallow active site pocket and buried catalytic cysteine. A water molecule trapped inside the PTP-binding loop makes close contacts both with main chain and with side chain atoms. The hydrodynamic radius (R(H)) of DeltaN60-C/S-DUSP26 measured from velocity sedimentation analysis (R(H) approximately 22.7 A) and gel filtration chromatography (R(H) approximately 21.0 A) is consistent with an approximately 18 kDa globular monomeric protein. Instead in crystal, DeltaN60-C/S-DUSP26 is more elongated (R(H) approximately 37.9 A), likely because of the extended conformation of C-terminal helix alpha9, which swings away from the phosphatase core to generate a highly basic surface. As in the case of phosphatase MKP-4, we propose that a substrate-induced conformational change, possibly involving rearrangement of helix alpha9 with respect to the phosphatase core, allows DUSP26 to adopt a catalytically active conformation. The structural characterization of DUSP26 presented in this paper provides the first atomic insight into this disease-associated phosphatase.
PDB ID: 4HRFDownload
MMDB ID: 106948
PDB Deposition Date: 2012/10/27
Updated in MMDB: 2013/06
Experimental Method:
x-ray diffraction
Resolution: 1.68  Å
Source Organism:
Similar Structures:
Biological Unit for 4HRF: tetrameric; determined by author
Molecular Components in 4HRF
Label Count Molecule
Proteins (4 molecules)
4
Dual Specificity Protein Phosphatase 26(Gene symbol: DUSP26)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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