title: Tyrosine phosphorylation of the Lyn Src homology 2 (SH2) domain modulates its binding affinity and specificity.
abstract: 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 Y(194) 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.
authors.affiliation: From the ‡Molecular Structure and Function, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada; ‡‡Departments of Molecular Genetics, Medical Science Building, Room 4386, 1 King's College Circle, Toronto, ON M5S 1A8, Canada;
authors.forename: Lily L
authors.initials: LL
authors.lastname: Jin
authors.affiliation: §Cell Biology, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada; ¶The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada;
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Wybenga-Groot
authors.affiliation: From the ‡Molecular Structure and Function, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada;
authors.forename: Jiefei
authors.initials: J
authors.lastname: Tong
authors.affiliation: From the ‡Molecular Structure and Function, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada;
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.affiliation: ‖Medical Biophysics, University of Toronto, Medical Science Building, Room 4386, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; **The Princess Margaret Cancer Center, 610 University Avenue, M5G 2M9, Toronto, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: ‖Medical Biophysics, University of Toronto, Medical Science Building, Room 4386, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; **The Princess Margaret Cancer Center, 610 University Avenue, M5G 2M9, Toronto, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.affiliation: §Cell Biology, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada; ¶The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada; ‖Medical Biophysics, University of Toronto, Medical Science Building, Room 4386, 1 King's College Circle, Toronto, ON M5S 1A8, Canada;
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
authors.affiliation: From the ‡Molecular Structure and Function, The Hospital For Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada; ‡‡Departments of Molecular Genetics, Medical Science Building, Room 4386, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; **The Princess Margaret Cancer Center, 610 University Avenue, M5G 2M9, Toronto, Canada m.moran@utoronto.ca.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Moran
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology*; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000201:enzymology*; D019000:Phosphotyrosine / Q000378:metabolism*; D017433:Protein Structure, Secondary; D040901:Proteomics / Q000379:methods*; D013379:Substrate Specificity; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry*
chemical_list: D019000:Phosphotyrosine; D019061:src-Family Kinases