Crystal structure of human TMDP, a testis-specific dual specificity protein phosphatase: implications for substrate specificity.
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.
Kim
Seung Jun
SJ
Center for Cellular Switch Protein Structure, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
Jeong
Dae-Gwin
DG
Yoon
Tae-Sung
TS
Son
Jeong-Hee
JH
Cho
Somi Kim
SK
Ryu
Seong Eon
SE
Kim
Jae-Hoon
JH
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
D054637:Dual-Specificity Phosphatases; D010749:Phosphoprotein Phosphatases; D017027:Protein Tyrosine Phosphatases; D013912:Threonine; D014443:Tyrosine; C498627:DUSP13B protein, human