Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding.
Biochem J
; 465(1): 149-61, 2015 Jan 01.
Article
in En
| MEDLINE
| ID: mdl-25287889
ABSTRACT
Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase (Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell antigen receptor signalling respectively. They are recruited, via their tandem-SH2 (Src-homology domain 2) domains, to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of immune antigen receptors. Because of their critical roles in immune signalling, ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases. We show that three thiol-reactive small molecules can prevent the tandem-SH2 domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a specific cysteine residue in the phosphotyrosine-binding pocket of each protein (Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive to the presence of H2O2 and these two cysteine residues are also necessary for inhibition by H2O2. Our findings suggest a mechanism by which the reactive oxygen species generated during responses to antigen could attenuate signalling through these kinases and may also inform the development of ZAP-70 and Syk inhibitors that bind covalently to their SH2 domains.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphopeptides
/
Protein-Tyrosine Kinases
/
Src Homology Domains
/
Cysteine
/
Intracellular Signaling Peptides and Proteins
/
ZAP-70 Protein-Tyrosine Kinase
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Biochem J
Year:
2015
Document type:
Article
Affiliation country:
United States