Babon Jeffrey J, McManus Edward J, Yao Shenggen, DeSouza David P, Mielke Lisa A, Sprigg Naomi S, Willson Tracy A, Hilton Douglas J, Nicola Nicos A, Baca Manuel, Nicholson Sandra E, Norton Raymond S
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050, Victoria, Australia.
Mol Cell. 2006 Apr 21;22(2):205-16. doi: 10.1016/j.molcel.2006.03.024.
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.
SOCS3对于调节细胞对细胞因子（如G-CSF和IL-6）反应的程度、持续时间和特异性至关重要。在此，我们描述了SOCS3的溶液结构，这是首个确定的任何SOCS蛋白的结构，它与来自IL-6受体信号亚基gp130的含磷酸酪氨酸肽形成复合物。复合物的结构表明，七个肽残基形成了一个主要为疏水性的结合基序。SOCS3 SH2结构域之外的区域对于配体结合很重要，特别是紧邻SH2结构域N端的一个由15个残基组成的α螺旋与磷酸酪氨酸结合环直接接触，并部分决定了其几何形状。SH2结构域本身很特别，因为它包含一个35个残基的无结构PEST基序插入序列，该序列对于抑制STAT并非必需。PEST基序增加了SOCS3的周转并影响其降解途径，这意味着它在细胞内具有重要的调节作用。
