Hydrophobic interaction between the SH2 domain and the kinase domain is required for the activation of Csk
- PMID: 20434462
- DOI: 10.1016/j.jmb.2010.04.045
Hydrophobic interaction between the SH2 domain and the kinase domain is required for the activation of Csk
Abstract
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. To study the importance of this interaction for the SH2-domain-mediated activation of Csk, we mutated the amino acid residues forming the contacts between the SH2 domain and the beta3-alphaC loop. The mutation of the beta3-alphaC loop Ala228 to glycine and of the SH2 domain Tyr116, Tyr133, Leu138, and Leu149 to alanine resulted in the inability of the SH2 domain ligand to activate Csk. Furthermore, the overexpressed Csk mutants A228G, Y133A/Y116A, L138A, and L149A were unable to efficiently inactivate endogenous Src in human embryonic kidney 293 cells. The results suggest that the SH2-domain-mediated activation of Csk is dependent on the binding of the beta3-alphaC loop Ala228 to the hydrophobic pocket formed by the side chains of Tyr116, Tyr133, Leu138, and Leu149 on the surface of the SH2 domain.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
Similar articles
-
The 2.35 A crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions.J Mol Biol. 1997 Dec 19;274(5):757-75. doi: 10.1006/jmbi.1997.1426. J Mol Biol. 1997. PMID: 9405157
-
Structural basis for domain-domain communication in a protein tyrosine kinase, the C-terminal Src kinase.J Mol Biol. 2006 Apr 7;357(4):1263-73. doi: 10.1016/j.jmb.2006.01.046. Epub 2006 Feb 2. J Mol Biol. 2006. PMID: 16483606
-
Domain interactions in protein tyrosine kinase Csk.Biochemistry. 1999 Aug 24;38(34):11147-55. doi: 10.1021/bi990827+. Biochemistry. 1999. PMID: 10460171
-
SH2 domains: modulators of nonreceptor tyrosine kinase activity.Curr Opin Struct Biol. 2009 Dec;19(6):643-9. doi: 10.1016/j.sbi.2009.10.001. Epub 2009 Nov 18. Curr Opin Struct Biol. 2009. PMID: 19926274 Free PMC article. Review.
-
Regulation of the SRC family kinases by Csk.Int J Biol Sci. 2012;8(10):1385-97. doi: 10.7150/ijbs.5141. Epub 2012 Nov 1. Int J Biol Sci. 2012. PMID: 23139636 Free PMC article. Review.
Cited by
-
Domain interactions of C-terminal Src Kinase determined through NMR spectroscopy with segmental isotope labeling.Protein Cell. 2017 Jan;8(1):67-71. doi: 10.1007/s13238-016-0333-y. Protein Cell. 2017. PMID: 27815825 Free PMC article. No abstract available.
-
Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation.PLoS One. 2015 Jun 1;10(6):e0127724. doi: 10.1371/journal.pone.0127724. eCollection 2015. PLoS One. 2015. PMID: 26030592 Free PMC article.
-
Regulation of Ack1 localization and activity by the amino-terminal SAM domain.BMC Biochem. 2010 Oct 27;11:42. doi: 10.1186/1471-2091-11-42. BMC Biochem. 2010. PMID: 20979614 Free PMC article.
-
Distal loop flexibility of a regulatory domain modulates dynamics and activity of C-terminal SRC kinase (csk).PLoS Comput Biol. 2013;9(9):e1003188. doi: 10.1371/journal.pcbi.1003188. Epub 2013 Sep 5. PLoS Comput Biol. 2013. PMID: 24039559 Free PMC article.
-
Regulation of Src and Csk nonreceptor tyrosine kinases in the filasterean Ministeria vibrans.Biochemistry. 2014 Mar 4;53(8):1320-9. doi: 10.1021/bi4016499. Epub 2014 Feb 18. Biochemistry. 2014. PMID: 24520931 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous
