Tyrosine Phosphorylation of the Lyn Src Homology 2 (SH2) Domain Modulates Its Binding Affinity and Specificity

被引:30
作者
Jin, Lily L. [1 ,4 ]
Wybenga-Groot, Leanne E. [2 ,3 ]
Tong, Jiefei [1 ]
Taylor, Paul [1 ]
Minden, Mark D. [5 ,6 ]
Trudel, Suzanne [5 ,6 ]
McGlade, C. Jane [2 ,3 ,5 ]
Moran, Michael F. [1 ,4 ,6 ]
机构
[1] Hosp Sick Children, Mol Struct & Funct, Toronto, ON M5G 0A4, Canada
[2] Hosp Sick Children, Cell Biol, Toronto, ON M5G 0A4, Canada
[3] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 0A4, Canada
[4] Univ Toronto, Dept Med Genet, Toronto, ON M5S 1A8, Canada
[5] Univ Toronto, Med Biophys, Toronto, ON M5S 1A8, Canada
[6] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada
关键词
PHOSPHOTYROSYL PEPTIDE; CRYSTAL-STRUCTURE; KINASE; PROTEIN; IDENTIFICATION; ACTIVATION; MOTIFS; RECOGNITION; ASSOCIATION; INHIBITION;
D O I
10.1074/mcp.M114.044404
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y-194 impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y194 on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases.
引用
收藏
页码:695 / 706
页数:12
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