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Review
. 2023 Mar 1:11:1148352.
doi: 10.3389/fcell.2023.1148352. eCollection 2023.

Dissection of the catalytic and regulatory structure-function relationships of Csk protein tyrosine kinase

Gongqin Sun  1 , Marina K Ayrapetov  1
Affiliations
Review

Dissection of the catalytic and regulatory structure-function relationships of Csk protein tyrosine kinase

Gongqin Sun et al. Front Cell Dev Biol. .

Abstract

Protein tyrosine kinases (PTKs) are a large enzyme family that regulates many cellular processes. The key to their broad role in signaling is their tunable substrate specificity and regulatory mechanisms that allow each to respond to appropriate regulatory signals and phosphorylate the correct physiological protein substrates. Thus, in addition to the general PTK catalytic platform, each PTK acquires unique structural motifs that confer a unique combination of catalytic and regulatory properties. Understanding the structural basis for these properties is essential for understanding and manipulating the PTK-based signaling networks in normal and cancer cells. C-terminal Src kinase (Csk) and its homolog, Csk-homologous kinase (Chk), phosphorylate Src family kinases on a C-terminal Tyr residue and negatively regulate their kinase activity. While this regulatory function is biologically essential, Csk and Chk have also been excellent model PTKs for dissecting the structural basis of PTK catalysis and regulation. In this article, we review the structure-function studies of Csk and Chk that shed light on the regulatory and catalytic mechanisms of protein tyrosine kinases in general.

Keywords: Csk and Chk; Src regulation; domain-domain interaction; kinase regulation; redox regulation; structure-function relationships; substrate recognition.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Structural organizations and tertiary structures of Csk and Src. (A). Domain organization of Csk and Src. The key domains and Tyr residues important for regulation are indicated. (B). Tertiary structure of Csk (PDB ID 1k9A, Ogawa et al., 2002). (C). Tertiary structure of Src when Tyr530 is phosphorylated (PDB ID 1FMK, Xu et al., 1999). (D). Tertiary structure of Src when Tyr530 is unphosphorylated (PDB ID 1Y57, Cowan-Jacob et al., 2005). The structural images are generated using Discovery Studio Visualizer.
FIGURE 2
FIGURE 2
Csk substrate docking site. (A). Csk ribbon structure with the key residues in the substrate docking site shown in ball and stick. The N-lobe, C-lobe and the active site cleft of Csk are indicated to show their positions relative to the substrate-docking site. (B). Surface structure of Csk and the substrate-docking site colored by the electric potential.
FIGURE 3
FIGURE 3
Domain-domain interactions in Csk. Important residues and motifs are indicated. Arg68, Trp 188, and the Csk SH2 domain are shown in space-filling model. The motifs of a-C, C-loop, and b4-5 turn constitutes an “on switch” in Src kinase domain. However, these motifs significantly diverged from those in Src to become a defective “on switch” that can only be turned on by interactions with the SH2 domain.
FIGURE 4
FIGURE 4
Csk motifs related to redox sensing. (A). Positions of Glu205 and the disulfide bond between Cys122 and Cys164 in Csk structure. (B). Alignment of the Gly-loop sequence in Src, Csk and FGFR family kinases. All four members of the FGFR kinases have the same sequence in the Gly-loop.
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Grants and funding

Research related to this review article carried out in the authors’ laboratory was supported by American Cancer Society Grants RSG-04-247-01-CDD and RSG CDD-106966, and National Institutes of Health Grant 1RO1CA111687. The authors are currently funded by a Department of Defense grant (award number: W81XWH-21-1-0598) on a research project not directly related to the topic in this article.