The tyrosine kinase Csk dimerizes through its SH3 domain

Nicholas M. Levinson, Patrick R. Visperas and John Kuriyan

Abstract / Illustrations from the paper / Coordinates

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.

Illustrations from the paper.

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Figure 1. - The SH3 domain of Csk is required for dimerization A) The constructs used in this paper. B) The results of size exclusion chromatography performed with the constructs shown in A. The elution volumes of molecular weight standards are indicated by black arrows.
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Figure 2. - The Csk SH3-SH3 dimer A) A representative SH3-SH3 dimer from the crystal structure of full-length Csk (PDB code: 1K9A). Residues in the interface are highlighted. B) The results of size exclusion chromatography performed with constructs of Csk bearing mutations in the putative dimer interface.
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Figure 3. - The Csk SH3-SH3 dimer is incompatible with the binding of ligands to the SH3 domain The solution structure of the SH3 domain of Csk in complex with the phosphatase-derived peptide PEP-3BP1 (pdb code 1JEG). The residues of Csk that are involved in the SH3-SH3 dimer interface are highlighted by sticks and black dots as in figure 2.
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Coordinates

Coordinates in the Protein Data Bank: 3FW1