Crystal structure of VHR, a dual-specificity phosphatase

The human VHR (VH1-Related) phosphatase is a member of the phosphatases that possess an in vitro dual specificity towards both phosphoseryl or phosphothreonyl (alkyl phosphates) and phosphotyrosyl (aryl phosphate) substrates. Other members of this protein family include cdc25, the mitogen-activated protein (MAP) kinase phosphatases MKP1, CL100, and PAC1. These dual- specificity phosphatases (DSPases) are important regulators of cell cycle control and mitogenic signal transduction. We have recently determined the crystal structure of VHR to 2.1 angstrom resolution by the method of multiple isomorphous replacement (MIR) using three heavy-atom derivatives. The structure comparison between the VHR and the known protein tyrosine phosphatases (PTPases), human PTP1B and Yersinia YOP51, reveals the structural basis for dual specificity of VHR: The short recognition region of VHR provides the shallower active-site pocket than the PTPase active site. This allows binding of the shorter phosphorylated serine or threonine as well as the longer phosphotyrosine. We propose that other DSPases fold into the structures similar to the VHR, and that their recognition regions are relatively short comparing to the PTPases. These allow a greater accessibility to their active sites and govern their dual specificity.