The protein tyrosine phosphatases (PTPases) and the dual specific phosphatases share amino acid sequence identity, however the two families of proteins have distinct substrate specificities. The PTPases will hydrolyze phosphate from phospho-Tyr containing proteins while the dual specific phosphatases will hydrolyze phosphate from phospho-Ser/Thr and phospho-Tyr containing substrates. These two enzyme families are remarkable catalysts which have important roles in a variety of biological processes. The PTPases appear to regulate the activities of receptors such as insulin and the platelet-derived growth factor receptor. A bacterial PTPase has been shown to be a virulence determinant in the pathogenic bacteria responsible for the Plague or the Black death. The dual specific phosphatases include the cell cycle regulator, cdc25, which functions to dephosphorylate cdc2. This family of catalysts play important roles in cell growth and cell division. The dual specific phosphatases are also present in pathogenic viruses, such as vaccinia as well as in smallpox virus. One of the goals outlined in this proposal is to understand the structure and function of the PTPase. We will use kinetic, and mechanistic studies coupled with an X-ray structure (which is in progress) to develop a more complete picture of the catalytic mechanism of these proteins. The catalytic properties of invariant acidic residues (Asp, Glu), as well as invariant Arg residues present in all PTPases, will be examined. The goal is to define their role(s) in substrate binding and/or catalysis. We will also determine if the bacterial and mammalian PTPases use a common catalytic strategy. Studies on the dual specific phosphatases will focus on obtaining one member of this family in large quantities for structural and functional studies (the dual specific phosphatase we have targeted in these studies is Vaccinia H 1 Related phosphatase; VHR). Efforts will be directed at obtaining crystals suitable for an X-ray structure determination. This information will likely lead to a greater understanding of the catalytic properties of the entire family of dual specific phosphatases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Biochemistry Study Section (BIO)
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Blondel, Olivier
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Banerjee, Sourav; Ji, Chenggong; Mayfield, Joshua E et al. (2018) Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2. Proc Natl Acad Sci U S A 115:8155-8160
Zhang, Hui; Zhu, Qinyu; Cui, Jixin et al. (2018) Structure and evolution of the Fam20 kinases. Nat Commun 9:1218
Qiu, Yimin; Poppleton, Erik; Mekkat, Arya et al. (2018) Enzymatic Phosphorylation of Ser in a Type I Collagen Peptide. Biophys J 115:2327-2335
Wang, Xiaorong; Cimermancic, Peter; Yu, Clinton et al. (2017) Molecular Details Underlying Dynamic Structures and Regulation of the Human 26S Proteasome. Mol Cell Proteomics 16:840-854
Pollak, Adam J; Haghighi, Kobra; Kunduri, Swati et al. (2017) Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia. Proc Natl Acad Sci U S A 114:9098-9103
Cui, Jixin; Zhu, Qinyu; Zhang, Hui et al. (2017) Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding. Elife 6:
Nguyen, Kim B; Sreelatha, Anju; Durrant, Eric S et al. (2016) Phosphorylation of spore coat proteins by a family of atypical protein kinases. Proc Natl Acad Sci U S A 113:E3482-91
Guo, Xing; Wang, Xiaorong; Wang, Zhiping et al. (2016) Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis. Nat Cell Biol 18:202-12
Tagliabracci, Vincent S; Wiley, Sandra E; Guo, Xiao et al. (2015) A Single Kinase Generates the Majority of the Secreted Phosphoproteome. Cell 161:1619-32
He, Yantao; Guo, Xing; Yu, Zhi-Hong et al. (2015) A potent and selective inhibitor for the UBLCP1 proteasome phosphatase. Bioorg Med Chem 23:2798-809

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