The Structure of SOCS3 Reveals the Basis of the Extended SH2 Domain Function and Identifies an Unstructured Insertion That Regulates Stability

Abstract

SOCS3 is essential for regulating the extent, duration, and specificity of cellular responses to cytokines such as G-CSF and IL-6. Here we describe the solution structure of SOCS3, the first structure determined for any SOCS protein, in complex with a phosphotyrosine-containing peptide from the IL-6 receptor signaling subunit gp130. The structure of the complex shows that seven peptide residues form a predominantly hydrophobic binding motif. Regions outside the SOCS3 SH2 domain are important for ligand binding, in particular, a single 15 residue alpha helix immediately N-terminal to the SH2 domain makes direct contacts with the phosphotyrosine binding loop and, in part, determines its geometry. The SH2 domain itself is remarkable in that it contains a 35 residue unstructured PEST motif insertion that is not required for STAT inhibition. The PEST motif increases SOCS3 turnover and affects its degradation pathway, implying that it has an important regulatory role inside the cell.

Cloning of common carp SOCS-3 gene and its expression during embryogenesis, GH-transgene and viral infection

“…Although the KIR domains of teleost SOCS-3s are much longer in length than those of mammalian, bird and amphibian SOCS-3s, the KIR function of teleost SOCS-3s is unclear. Furthermore, the mammalian SOCS-3 molecules contain a well conserved PEST motif that increases SOCS-3 turnover and affects its protein stability [29]. However, no PEST motif was found in the SOCS-3 molecules from the other species including amphibians, birds and the known teleosts.…”

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

“…The SOCS-SH2 domain sits immediately upstream of the SOCS box and is distinguished by an N-terminal a-helix termed the extended SH2 subdomain (ESS), which stabilises the phosphotyrosine-binding loop (18,25). Binding of the SH2 domain to phosphorylated residues within the receptor complex brings the SOCS box-associated E3 ubiquitin ligase into the vicinity of its substrate.…”

Suppressor of Cytokine Signaling 2 Is a Feedback Inhibitor of TLR-Induced Activation in Human Monocyte-Derived Dendritic Cells

“…First, SOCS proteins bind competitively to their target proteins, thus displacing and sequestering the signaling intermediates away from their respective receptors, thereby inhibiting downstream signaling. The common SH2 domain mediates binding to phosphotyrosine residues, whereas the extended SH2 subdomain confines the substrate specificity (6). Second, the shared KIR motif of SOCS1 and SOCS3 directly inhibits JAK activity, apparently by acting as a pseudosubstrate for the kinase (7).…”