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Type: Journal article
Title: Defining the substrate specificity determinants recognized by the active site of C-terminal Src kinase-homologous kinase (CHK) and identification of β-synuclein as a potential CHK physiological substrate
Other Titles: Defining the substrate specificity determinants recognized by the active site of C-terminal Src kinase-homologous kinase (CHK) and identification of beta-synuclein as a potential CHK physiological substrate
Author: Ia, K.
Jeschke, G.
Deng, Y.
Kamaruddin, M.
Williamson, N.
Scanlon, D.
Culvenor, J.
Hossain, M.
Purcell, A.
Liu, S.
Zhu, H.
Turk, B.
Catimel, B.
Cheng, H.
Citation: Biochemistry, 2011; 50(31):6667-6677
Publisher: American Chemical Society
Issue Date: 2011
ISSN: 0006-2960
Statement of
m K. Ia, Grace R. Jeschke, Yang Deng, Mohd Aizuddin Kamaruddin, Nicholas A. Williamson, Denis B. Scanlon, Janetta G. Culvenor, Mohammed Iqbal Hossain, Anthony W. Purcell, Sheng Liu, Hong-Jian Zhu, Bruno Catimel, Benjamin E. Turk, and Heung-Chin Cheng
Abstract: C-Terminal Src kinase-homologous kinase (CHK) exerts its tumor suppressor function by phosphorylating the C-terminal regulatory tyrosine of the Src-family kinases (SFKs). The phosphorylation suppresses their activity and oncogenic action. In addition to phosphorylating SFKs, CHK also performs non-SFK-related functions by phosphorylating other cellular protein substrates. To define these non-SFK-related functions of CHK, we used the “kinase substrate tracking and elucidation” method to search for its potential physiological substrates in rat brain cytosol. Our search revealed β-synuclein as a potential CHK substrate, and Y127 in β-synuclein as the preferential phosphorylation site. Using peptides derived from β-synuclein and positional scanning combinatorial peptide library screening, we defined the optimal substrate phosphorylation sequence recognized by the CHK active site to be E-x-[Φ/E/D]-Y-Φ-x-Φ, where Φ and x represent hydrophobic residues and any residue, respectively. Besides β-synuclein, cellular proteins containing motifs resembling this sequence are potential CHK substrates. Intriguingly, the CHK-optimal substrate phosphorylation sequence bears little resemblance to the C-terminal tail sequence of SFKs, indicating that interactions between theCHKactive site and the local determinants near theC-terminal regulatory tyrosine of SFKs play only aminor role in governing specific phosphorylation of SFKs by CHK.Our results imply that recognition of SFKs by CHK is mainly governed by interactions between motifs located distally from the active site of CHK and determinants spatially separate from the C-terminal regulatory tyrosine in SFKs. Thus, besides assisting in the identification of potentialCHKphysiological substrates, our findings shed new light on howCHKrecognizes SFKs and other protein substrates.
Keywords: Cytosol
src-Family Kinases
Peptide Library
Amino Acid Sequence
Amino Acid Motifs
Catalytic Domain
src Homology Domains
Structural Homology, Protein
Substrate Specificity
Molecular Sequence Data
Protein-Tyrosine Kinases
HEK293 Cells
CSK Tyrosine-Protein Kinase
Description: Published: June 23, 2011
Rights: Copyright © 2011 American Chemical Society
DOI: 10.1021/bi2001938
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