首页> 外文期刊>The Journal of biological chemistry >Structural Basis for c-KIT Inhibition by the Suppressor of Cytokine Signaling 6 (SOCS6) Ubiquitin Ligase
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Structural Basis for c-KIT Inhibition by the Suppressor of Cytokine Signaling 6 (SOCS6) Ubiquitin Ligase

机译:细胞因子信号6(SoCs6)泛素连接酶抑制抑制的C-kit抑制的结构基础

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The c-KIT receptor tyrosine kinase mediates the cellular response to stem cell factor (SCF). Whereas c-KIT activity is important for the proliferation of hematopoietic cells, melanocytes and germ cells, uncontrolled c-KIT activity contributes to the growth of diverse human tumors. Suppressor of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can interact with c-KIT and suppress c-KIT-dependent pathways. Here, we analyzed the molecular mechanisms that determine SOCS6 substrate recognition. Our results show that the SH2 domain of SOCS6 is essential for its interaction with c-KIT pY568. The 1.45-? crystal structure of SOCS6 SH2 domain bound to the c-KIT substrate peptide (c-KIT residues 564–574) revealed a highly complementary and specific interface giving rise to a high affinity interaction (Kd = 0.3 μm). Interestingly, the SH2 binding pocket extends to substrate residue position pY+6 and envelopes the c-KIT phosphopeptide with a large BG loop insertion that contributes significantly to substrate interaction. We demonstrate that SOCS6 has ubiquitin ligase activity toward c-KIT and regulates c-KIT protein turnover in cells. Our data support a role of SOCS6 as a feedback inhibitor of SCF-dependent signaling and provides molecular data to account for target specificity within the SOCS family of ubiquitin ligases.
机译:C-kit受体酪氨酸激酶介导细胞反应对干细胞因子(SCF)。然而,C-kit活性对于造血细胞的增殖是重要的,Melanocytes和胚芽细胞,不受控制的c-kit活性有助于各种人类肿瘤的生长。细胞因子信令6(SOCS6)的抑制剂是E3泛素连接酶的SOC系列的成员,其可以与C-kit相互作用并抑制C-kit依赖性途径。在这里,我们分析了确定SOCS6基板识别的分子机制。我们的结果表明,SOCS6的SH2域对其与C-KIT PY568的互动至关重要。 1.45-?与C-kit底物肽结合的SOCS6 SH2结构域的晶体结构(C-kit残基564-574)揭示了高度互补和特异性界面,从而产生高亲和力相互作用(Kd =0.3μm)。有趣的是,SH2结合口袋延伸到衬底残留位置PY + 6,并用大的BG环形插入包围C-kit磷肽,其有助于显着呈现衬底相互作用。我们证明SOCS6对C-kit的泛素连接酶活性并调节细胞中的C-kit蛋白质周转。我们的数据支持SOCS6作为SCF依赖信号传导的反馈抑制剂的作用,并提供分子数据,以考虑遍在蛋白蛋白皮酶的SOC系列中的目标特异性。

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