title: Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variants S201F and R266W.
abstract: The Lymphoid specific tyrosine phosphatase (Lyp) has elicited tremendous research interest due to the high risk of its missense mutation R620W in a wide spectrum of autoimmune diseases. While initially characterized as a gain-of-function mutant, R620W was thought to lead to autoimmune diseases through loss-of-function in T cell signaling by a recent study. Here we investigate the biochemical characters and T cell signaling functions of two uncharacterized Lyp variants S201F and R266W, together with a previously characterized Lyp variant R263Q, which had reduced risk in several autoimmune diseases, including systemic lupus erythematosus (SLE), ulcerative colitis (UC) and rheumatoid arthritis (RA). Our kinetic and functional studies of R263Q polymorphism basically reproduced previous findings that it was a loss-of-function mutant. The other variant S201F reduced Lyp phosphatase activity moderately and decreased Lyp function in T cell slightly, while R266W severely impaired phosphatase activity and was a loss-of-function variant in T cell signaling. A combined kinetic and structure analysis suggests that the R266W variant may decrease its phosphatase activity through perturbing either the Q-loop or the WPD loop of Lyp. As both R266W and R263Q significantly change their phosphatase activity and T cell functions, future work could be considered to evaluate these mutants in a broader spectrum of autoimmune diseases.
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Xuanren
authors.initials: X
authors.lastname: Shi
authors.forename: Lichao
authors.initials: L
authors.lastname: Zhu
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Qiji
authors.initials: Q
authors.lastname: Liu
authors.forename: Fan-Guo
authors.initials: FG
authors.lastname: Meng
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Sun
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009596:Nitrophenols / Q000737:chemistry / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology
chemical_list: D009596:Nitrophenols; D010750:Phosphoproteins; D016392:Proto-Oncogene Proteins pp60(c-src); C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22