Crystal structure of the catalytic domain of human DUSP5, a dual specificity MAP kinase protein phosphatase

Introduction.Mitogen-activated protein kinases (MAPKs) mediate a variety of cell signals regulating cell growth, differentiation, transcription, and metabolism.MAPKs are fully activated by dual phosphorylation on tyrosine and threonine in their activation loops.This process is thought to be counteracted by a family of proteins termed dual-specificity protein tyrosine phosphatases (DSPs).Inadequate production or action of MAPKs or DSPs has been associated with diverse human disorders, including cancer, diabetes, and autoimmune diseases.[1][2][3][4] DSPs are a subclass of the protein tyrosine phosphatase (PTP) superfamily that shares a highly conserved active site motif and a common catalytic mechanism.The members of human DSP family, which dephosphorylate both phospho-serine/threonine and phosphotyrosine substrates, can be divided into dual-specificity mitogen-activated protein kinase phosphatases (DS-MKPs) and atypical DSPs.Atypical DSPs contain only catalytic domain, whereas DS-MKPs have an additional N-terminal MAPK binding domain that is responsible for the substrate recognition.5 Dual-specificity phosphatase 5 (DUSP5) belongs to DS-MKP subfamily and preferentially dephosphorylates extracellular signal-regulated kinase (ERK) in vitro.6 DUSP5 can be distinguished from other DSPs by its mRNA regulation, response to extracellular stimuli, and tissue-specific expression, suggesting that DUSP5 play a specific role in the cell.Recently, the transcription of the DUSP5 gene was shown to be directly regulated by p53, and the overexpression of DUSP5 was shown to suppress the growth of several types of human cancer cells.7 More potent and selective inhibitors are needed to elucidate the specific cellular function of individual DSPs and as candidates for clinical use. 3 The development of such inhibitors has been hampered, at least in part, by a lack of structural information.Among the 11 members of DS-MKPs of the human genome, only PAC1 and MKP3 have been structurally characterized.8,9 These, however, have substantially different conformation than PTPs in active conformations, 3 as deduced from their structures with bound substrates or inhibitors.Here, we report the crystal structure of catalytic domain of human DUSP5 (DUSP5-C) at 2.7 A ˚resolution.The detailed structure revealed that DUSP5-C adopts an active conformation of PTP.In addition, DUSP5-C forms dimers through a novel head-to-tail association.These structural features of DUSP5 indicate that DUSP5 has a different mechanism of substrate recognition than other DS-MKPs.This information should pave the way for the rational design of specific inhibitors.