SH2 Domains from Suppressor of Cytokine Signaling-3 and Protein Tyrosine Phosphatase SHP-2 Have Similar Binding Specificities

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• 作者：David De Souza ; Louis J. Fabri ; Andrew Nash ; Douglas J. Hilton ; Nicos A. Nicola ; and Manuel Baca
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：July 23, 2002
• 年：2002
• 卷：41
• 期：29
• 页码：9229 - 9236
• 全文大小：78K
• 年卷期：v.41,no.29(July 23, 2002)
• ISSN：1520-4995

文摘

Suppressor of cytokine signaling-3 (SOCS-3) and the protein tyrosine phosphatase SHP-2both regulate signaling by cytokines of the interleukin-6 family, and this is dependent upon recruitmentto tyrosine 757 in the shared cytokine receptor subunit gp130. To better explore the overlap in ligandbinding specificities exhibited by these two signaling regulators, we have mapped the phosphopeptidebinding preferences of the SH2 domains from SOCS-3 and SHP-2. Degenerate phosphopeptide librarieswere screened against recombinantly produced SH2 domains to determine the sequences of optimalphosphopeptide 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 basedon the consensus motifs and found that these bound to SOCS-3 and SHP-2 with high affinity. Finally, wehave compared the affinity of SOCS-3 for binding to phosphopeptides representing putative docking sitesin the gp130, leptin and erythropoietin receptors. While SOCS-3 binds with much higher affinity to agp130 phosphopeptide than to phosphopeptides derived from the other receptors, multiple SOCS-3 bindingsites are predicted to exist in the leptin and erythropoietin receptors which may compensate for weakerbinding to individual sites.