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Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases, and are intimately involved in the regulation of diverse parameters of cellular signaling and essential biological processes. DUSP28 is one of the DUSP subfamily members that is known to be implicated in the progression of hepatocellular and pancreatic cancers, and its biological functions and enzymatic characteristics are mostly unknown. Herein, we present the crystal structure of human DUSP28 determined to 2.1 Å resolution. DUSP28 adopts a typical DUSP fold, which is composed of a central β-sheet covered by α-helices on both sides and contains a well-ordered activation loop, as do other enzymatically active DUSP proteins. The catalytic pocket of DUSP28, however, appears hardly accessible to a substrate because of the presence of nonconserved bulky residues in the protein tyrosine phosphatase signature motif. Accordingly, DUSP28 showed an atypically low phosphatase activity in the biochemical assay, which was remarkably improved by mutations of two nonconserved residues in the activation loop. Overall, this work reports the structural and biochemical basis for understanding a putative oncological therapeutic target, DUSP28, and also provides a unique mechanism for the regulation of enzymatic activity in the DUSP subfamily proteins.

Receptor-type protein tyrosine phosphatases (RPTPs) belong to the protein tyrosine phosphatase (PTP) family and play a critical role in cell signaling. RPTPH, a type of RPTP, consists of long extracellular domains, a transmembrane domain, and a single intracellular domain with phosphatase activity. RPTPH is involved in phosphorylation of target proteins involved in the AKT signaling pathway and regulates T-cell function and cell apoptosis. The protein is also implicated in progression of colorectal and lung cancers. Despite the importance of RPTPH in tumor-related cell signaling and therapeutic drug development, the structure of this enzyme has not yet been determined. We overexpressed, purified, and crystallized the catalytic domain of RPTPH. The RPTPH crystal diffracted at a resolution of 1.56 Å. It belonged to the space group P3 2 with unit cell parameters a = b = 56.46 Å, c = 80.45 Å, α = β = 90°, and γ = 120°.

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