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

• Published in: Molecular & cellular proteomics 2015-03, Vol.14 (3), p.695-706
• Main Authors: Jin, Lily L., Wybenga-Groot, Leanne E., Tong, Jiefei, Taylor, Paul, Minden, Mark D., Trudel, Suzanne, McGlade, C. Jane, Moran, Michael F.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Cell Line, Tumor; Conserved Sequence; Crystallography, X-Ray; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemia, Myeloid, Acute - enzymology; Models, Molecular; Multiple Myeloma - enzymology; Phosphotyrosine - metabolism; Protein Structure, Secondary; Proteomics - methods; src Homology Domains; src-Family Kinases - chemistry; Substrate Specificity
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1074/mcp.M114.044404

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 Y194 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.