Structural elements and allosteric mechanisms governing regulation and catalysis of CSK-family kinases and their inhibition of Src-family kinases

Abstract

C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors constraining the activity of the oncogenic Src-family kinases (SFKs) in cells. Both kinases suppress SFKs by selectively phosphorylating their consensus C-terminal regulatory tyrosine. In addition to phosphorylation, CHK can suppress SFKs by a unique non-catalytic inhibitory mechanism that involves tight binding of CHK to SFKs to form stable complexes. In this review, we discuss how allosteric regulators, phosphorylation, and inter-domain interactions interplay to govern the activity of CSK and CHK and their ability to inhibit SFKs. In particular, based upon the published results of structural and biochemical analysis of CSK and CHK, we attempt to chart the allosteric networks in CSK and CHK that govern their catalysis and ability to inhibit SFKs. We also discuss how the published three-dimensional structure of CSK complexed with an SFK member sheds light on the structural basis of substrate recognition by protein kinases.

Keywords::

• Protein kinase
• Src-family kinases
• CSK
• CHK
• allosteric regulation
• catalysis

Declaration of interest: The authors' work described in this review was supported by research grants from the National Health and Medical Research Council of Australia and Cancer Council Victoria. RM is a recipient of the Dowd Neuroscience Postgraduate Research Fellowship and Australian Institute of Nuclear Science and Engineering Postgraduate Research Award. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Notes

^* The phosphorylation site is referred to as P site. For the amino acids located at the N-terminal side of the p site in protein/peptide substrates, they are referred to as P − 1, P − 2, P − 3, etc. For those located at the C-terminal side of the P site, they are referred to as P+1, P+2, P+3, etc.

^† In this sequence, +represents a lysine or arginine residue; x represents any one of the amino acid residues; and Φ represents a hydrophobic residue.