2VIF

Crystal structure of SOCS6 SH2 domain in complex with a c-KIT phosphopeptide

2VIF の概要

• エントリーDOI: 10.2210/pdb2vif/pdb
• 関連するPDBエントリー: 1PKG 1QZJ 1QZK 1R01 1T45 1T46
• 分子名称: SUPPRESSOR OF CYTOKINE SIGNALLING 6, MAST/STEM CELL GROWTH FACTOR RECEPTOR, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: growth regulation, signal transduction inhibitor, kit regulator, phosphotyrosine, signaling protein
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P10721
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 17330.08

構造登録者

Bullock, A.,Pike, A.C.W.,Savitsky, P.,Keates, T.,Pilka, E.S.,von Delft, F.,Edwards, A.,Weigelt, J.,Arrowsmith, C.H.,Knapp, S. (登録日: 2007-11-30, 公開日: 2007-12-25, 最終更新日: 2024-11-20)

主引用文献

Zadjali, F.,Pike, A.C.W.,Vesterlund, M.,Sun, J.,Wu, C.,Li, S.S.,Ronnstrand, L.,Knapp, S.,Bullock, A.,Flores-Morales, A.
Structural Basis for C-Kit Inhibition by the Suppressor of Cytokine Signaling 6 (Socs6) Ubiquitin Ligase.
J.Biol.Chem., 286:480-, 2011

PubMed Abstract: 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-Å 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 (K(d) = 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.

PubMed: 21030588
DOI: 10.1074/JBC.M110.173526

実験手法

X-RAY DIFFRACTION (1.45 Å)