Hydrophobic interaction between the SH2 domain and the kinase domain is required for the activation of Csk.

The protein tyrosine kinase C-terminal Src kinase (Csk) is activated by the engagement of its Src homology (SH) 2 domain. However, the molecular mechanism required for this is not completely understood. The crystal structure of the active Csk indicates that Csk could be activated by contact between the SH2 domain and the beta3-alphaC loop in the N-terminal lobe of the kinase domain.

Conserved hydrophobicity in the SH2-kinase linker is required for catalytic activity of Csk and CHK.

The crystal structure of full-length Csk (C-terminal Src kinase) molecules shows a hydrophobic interaction between the SH2-kinase linker residue Phe183 and the alphaC-helix of the catalytic domain. To study the possible involvement of this contact in the regulation of the activity of Csk and CHK (Csk homologous kinase), a Csk SH2-kinase linker deletion mutant, Csk Phe183 and CHK Leu223 point mutants were analyzed. It was observed that a residue with a long hydrophobic side chain in position 183 (Csk) and 223 (CHK) is required to sustain the catalytic activity of Csk and CHK.