PTPN22: Human protein tyrosine phosphatase, non-receptor type 22
PDB Code: 2P6X
PTPN22, also known as lymphoid-specific protein tyrosine phosphatase (LYP) or pest-domain phosphatase (PEP) belongs together with PTPN18 and PTPN12 to the non-receptor class 4 subfamily of tyrosine phoshatases. Apart from the phosphatase domain PTPN22 contains four proline-rich SH3 domain binding motifs and an NXXY motif.
PTPN22 is a negative regulator in the T-cell activation and a recent report demonstrated that PTPN22 is a "linkage-proven" autoimmunity gene associated with susceptibility to several autoimmune diseases, including type 1 diabetes, rheumatoid arthritis as well as sensitivity to bacterial infection. R620W polymorphism leads to a disrupted interaction site for the SH3 domain of the tyrosine kinase Csk has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and graves thyroiditis. Interestingly, primary T cells from patients homozygous for R620W produced less interleukin (IL)-2 following CD3 stimulation compared with individuals containing the wild-type gene, possibly owing to increased phosphatase activity of PTPN22.
RNAi knockdown of PTPN22 message in human T cell lines results in increased TCR signaling. PTPN22 dephosphorylates several molecules involved in T cell receptor signaling including LCK, Zap70, and the CD3 ε and TCR ζ chains. In addition, PTPN22 knockout mice develop splenomegaly and lymphadenopathy at the age of 6 month.
Furthermore, the PTPN22 gene has been mapped to chromosome 1p13, a region associated with rearrangements in solid and hematopoietic tumors; it may play an antagonistic role in signaling by the Bcr-Abl fusion protein. Here we determined the crystal structure of the catalytic domain of PTPN22 at 1.8 Å resolution.
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