The family-wide structure and function of human dual-specificity protein phosphatases

Abstract

Dual-specificity protein phosphatases (DUSPs), which dephosphorylate both phosphoserine/threonine and phosphotyrosine, play vital roles in immune activation, brain function and cell-growth signalling. A family-wide structural library of human DUSPs was constructed based on experimental structure determination supplemented with homology modelling. The catalytic domain of each individual DUSP has characteristic features in the active site and in surface-charge distribution, indicating substrate-interaction specificity. The active-site loop-to-strand switch occurs in a subtype-specific manner, indicating that the switch process is necessary for characteristic substrate interactions in the corresponding DUSPs. A comprehensive analysis of the activity-inhibition profile and active-site geometry of DUSPs revealed a novel role of the active-pocket structure in the substrate specificity of DUSPs. A structure-based analysis of redox responses indicated that the additional cysteine residues are important for the protection of enzyme activity. The family-wide structures of DUSPs form a basis for the understanding of phosphorylation-mediated signal transduction and the development of therapeutics.

DUSP28 contributes to human hepatocellular carcinoma via regulation of the p38 MAPK signaling

“…the DuSPs constitute a heterogeneous group of cysteine-based protein tyrosine phosphatases. as a subgroup of DuSPs, the small-size atypical DuSPs are generally smaller and lack the cH2 domain in the n-terminus that is common to the typical MKPs (13). a number of studies on small atypical DuSPs in the past few decades has enhanced our understanding of their function in cancer and indicated their potential as anti-cancer therapy targets.…”

“…Dual-specificity phosphatases (DuSPs) are a heterogeneous group of protein phosphatases that can regulate the activity of mitogen-activated protein kinases (MaPKs), which play a critical role in the control of cell growth and survival in phy siological and pathological processes, including cancer (11,12). DUSPs can be classified into six major groups based on the presence of specific domains and sequence similarity, including the MaPK phosphatases (MKPs), as well as a group of small-size atypical DuSPs (13). as their name indicates, MKPs can dephosphorylate MaPK proteins erK, jnK and p38 with specificity.…”

Structural Insight into the Critical Role of the N-Terminal Region in the Catalytic Activity of Dual-Specificity Phosphatase 26

“…In addition, we performed enzyme kinetics analysis with DUSP26-N and compared the kinetic parameters with those of VH1-related DUSP (VHR), DUSP13b, and DUSP14 [27] (Table 1). The K cat /K m value of DUSP26-N was 100-fold smaller than that of VHR, but was comparable to that of DUSP13b, which is known as the DUSP that is most analogous to DUSP26 according to phylogenetic analysis [2, 28]. …”

“…Although the N-terminal α1-helices are found in a subgroup of atypical DUSPs (from the G4 group in the phylogenetic tree of human DUSPs) [28], there is a noticeable difference in their orientations. In Dusp27 and VH1, the N-terminal α1-helices project away from the catalytic core to mediate dimerization with the other monomer via domain swapping (Fig 5A and 5C) [31, 33].…”

Crystal structure of the human dual specificity phosphatase 1 catalytic domain

“…DUSPs can dephosphorylate both phosphotyrosine and phosphothreonine in the TxY motif of MAPKs . The 26 unique DUSPs encoded by the human genome are classified either as MAPK phosphatases (MKPs) or atypical DUSPs . The MKPs are composed of an N‐terminal non‐catalytic MAPK‐binding domain (MKBD) and a highly conserved C‐terminal catalytic domain (CD).…”