SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities
- Author(s)
- De Souza, D; Fabri, LJ; Nash, A; Hilton, DJ; Nicola, NA; Baca, M;
- Details
- Publication Year 2002-07-23,Volume 41,Issue #29,Page 9229-9236
- Journal Title
- BIOCHEMISTRY
- Publication Type
- Journal Article
- Abstract
- Suppressor of cytokine signaling-3 (SOCS-3) and the protein tyrosine phosphatase SHP-2 both regulate signaling by cytokines of the interleukin-6 family, and this is dependent upon recruitment to tyrosine 757 in the shared cytokine receptor subunit gp130. To better explore the overlap in ligand binding specificities exhibited by these two signaling regulators, we have mapped the phosphopeptide binding preferences of the SH2 domains from SOCS-3 and SHP-2. Degenerate phosphopeptide libraries were screened against recombinantly produced SH2 domains to determine the sequences of optimal phosphopeptide ligands. We found that the consensus ligand binding motif for SOCS-3 was pY-(S/A/V/Y/F)-hydrophobic-(V/I/L)-hydrophobic-(H/V/I/Y), while the consensus motif for SHP-2 was pY-(S/T/A/V/I)-X-(V/I/L)-X-(W/F). We validated these data through the design of phosphopeptide ligands based on the consensus motifs and found that these bound to SOCS-3 and SHP-2 with high affinity. Finally, we have compared the affinity of SOCS-3 for binding to phosphopeptides representing putative docking sites in the gp130, leptin and erythropoietin receptors. While SOCS-3 binds with much higher affinity to a gp130 phosphopeptide than to phosphopeptides derived from the other receptors, multiple SOCS-3 binding sites are predicted to exist in the leptin and erythropoietin receptors which may compensate for weaker binding to individual sites.
- Publisher
- AMER CHEMICAL SOC
- Keywords
- AFFINITY PHOSPHOTYROSYL PEPTIDE; CRYSTAL-STRUCTURES; LEPTIN RECEPTOR; SOCS3; RECOGNITION; RECRUITMENT; KINASE; IDENTIFICATION; SH-PTP2; FAMILY
- Publisher's Version
- https://doi.org/10.1021/bi0259507
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2002-07-23 12:00:00