Interactions between the Fyn SH3-domain and adaptor protein Cbp/PAG derived ligands, effects on kinase activity and affinity

The FEBS Journal
Silje Anette SolheimTorunn Berge

Abstract

Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched domains is a transmembrane adaptor protein primarily involved in negative regulation of T-cell activation by recruitment of C-terminal Src kinase (Csk), a protein tyrosine kinase which represses Src kinase activity through C-terminal phosphorylation. Recruitment of Csk occurs via SH2-domain binding to PAG pTyr317, thus, the interaction is highly dependent on phosphorylation performed by the Src family kinase Fyn, which docks onto PAG using a dual-domain binding mode involving both SH3- and SH2-domains of Fyn. In this study, we investigated Fyn SH3-domain binding to 14-mer peptide ligands derived from Cbp/PAG-enriched microdomains sequence using biochemical, biophysical and computational techniques. Interaction kinetics and dissociation constants for the various ligands were determined by SPR. The local structural impact of ligand association has been evaluated using CD, and molecular modelling has been employed to investigate details of the interactions. We show that data from these investigations correlate with functional effects of ligand binding, assessed experimentally by kinase assays using full-length PAG proteins as substrates. The presented da...Continue Reading

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Citations

Jun 3, 2010·Frontiers in Bioscience (Scholar Edition)·Matthew J Loza, Raymond B Penn
Nov 12, 2013·Oncogene·M Hrdinka, V Horejsi
Nov 26, 2010·Biochimica Et Biophysica Acta·Kaare TeilumBirthe B Kragelund
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Oct 7, 2015·Frontiers in Immunology·Zachary J GerbecSubramaniam Malarkannan
Mar 10, 2009·Journal of the American Chemical Society·Jean-Philippe Demers, Anthony Mittermaier
Sep 5, 2009·Chembiochem : a European Journal of Chemical Biology·Rakesh Tiwari, Keykavous Parang
Nov 24, 2019·International Journal of Molecular Sciences·Poojitha SitaramMatthew J Riese
Jun 20, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dipak BaruaTomasz Lipniacki
Mar 23, 2019·Frontiers in Cell and Developmental Biology·Katarina IlicRodrigo Herrera-Molina

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