title: Regulation of lymphoid tyrosine phosphatase activity: inhibition of the catalytic domain by the proximal interdomain.
abstract: The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, recently emerged as a major player and candidate drug target for human autoimmunity. The enzyme includes a classical N-terminal protein tyrosine phosphatase catalytic domain and a C-terminal PEST-enriched domain, separated by an approximately 300-amino acid interdomain. Little is known about the regulation of LYP. Herein, by analysis of serial truncation mutants of LYP, we show that the phosphatase activity is strongly inhibited by protein regions C-terminal to the catalytic domain. We mapped the minimal inhibitory region to the proximal portion of the interdomain. We show that the activity of LYP is inhibited by an intramolecular mechanism, whereby the proximal portion of the interdomain directly interacts with the catalytic domain and reduces its activity.
authors: Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors: Yingge
authors: Y
authors: Liu
authors: Stephanie M
authors: SM
authors: Stanford
authors: Sonali P
authors: SP
authors: Jog
authors: Edoardo
authors: E
authors: Fiorillo
authors: Valeria
authors: V
authors: Orrú
authors: Lucio
authors: L
authors: Comai
authors: Nunzio
authors: N
authors: Bottini
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000201:enzymology*; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: D047428:Protein Kinase Inhibitors; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22