title: The tyrosine kinase Csk dimerizes through Its SH3 domain.
abstract: The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The latter modification is achieved by the tyrosine kinase Csk (C-terminal Src Kinase), but the complete inactivation of the Src family kinases also requires the dephosphorylation of the activation loop tyrosine. The SH3 domain of Csk recruits the tyrosine phosphatase PEP, allowing for the coordinated inhibition of Src family kinase activity. We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands. The formation of this dimer would therefore block the recruitment of tyrosine phosphatases and may have important implications for the regulation of Src kinase activity.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Levinson
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Visperas
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D002850:Chromatography, Gel; D003460:Crystallization; D019281:Dimerization; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains; D019061:src-Family Kinases
chemical_list: D008024:Ligands; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human