title: Crystal structure of human TMDP, a testis-specific dual specificity protein phosphatase: implications for substrate specificity.
abstract: The testis- and skeletal-muscle-specific dual-specificity phosphatase (TMDP) is a member of the dual-specificity phosphatase (DSP) subgroup of protein tyrosine phosphatases. TMDP has similar activities toward both tyrosine and threonine phosphorylated substrates, and is supposed to be involved in spermatogenesis. Here, we report the crystal structure of human TMDP at a resolution of 2.4 A. In spite of high sequence similarity with other DSPs, the crystal structure of TMDP shows distinct structural motifs and surface properties. In TMDP, the alpha1-beta1 loop, a substrate recognition motif is located further away from the active site loop in comparison to prototype DSP Vaccinia H1 related phophatase (VHR), which preferentially dephosphorylates tyrosine phosphorylated substrates and down-regulates MAP kinase signaling. Residues in the active site residues of TMDP are smaller in size and more hydrophobic than those of VHR. In addition, TMDP cannot be aligned with VHR in loop beta3-alpha4. These differences in the active site of TMDP result in a flat and wide pocket structure, allowing equal binding of phosphotyrosine and phosphothreonine substrates.
authors.affiliation: Center for Cellular Switch Protein Structure, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Dae-Gwin
authors.initials: DG
authors.lastname: Jeong
authors.forename: Tae-Sung
authors.initials: TS
authors.lastname: Yoon
authors.forename: Jeong-Hee
authors.initials: JH
authors.lastname: Son
authors.forename: Somi Kim
authors.initials: SK
authors.lastname: Cho
authors.forename: Seong Eon
authors.initials: SE
authors.lastname: Ryu
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D054637:Dual-Specificity Phosphatases; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity; D013737:Testis / Q000201:enzymology*; D013912:Threonine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D054637:Dual-Specificity Phosphatases; D010749:Phosphoprotein Phosphatases; D017027:Protein Tyrosine Phosphatases; D013912:Threonine; D014443:Tyrosine; C498627:DUSP13B protein, human