Molecular Mechanism of Inward Rectifier Potassium Channel 2.3 Regulation by Tax-Interacting Protein-1

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• 作者：Xiaojie Yan ; Hao Zhou ; Jinxiu Zhang ; Chaowei Shi ; Xingqiao Xie ; Yinan Wu ; Changlin Tian ; Yuequan Shen ; Jiafu Long
• 关键词：Tax-interacting protein-1 ; inwardly rectifying potassium channels ; Kir2.3 ; PDZ domain ; channel recycling
• 刊名：Journal of Molecular Biology
• 出版年：2009
• 出版时间：2 October 2009
• 年：2009
• 卷：392
• 期：4
• 页码：967-976
• 全文大小：1167 K

文摘

Inwardly rectifying potassium channel 2.3 (Kir2.3) is specifically targeted on the basolateral membranes of epithelial and neuronal cells, and it thus plays an important role in maintaining potassium homeostasis. Tax-interacting protein-1 (TIP-1), an atypical PDZ-domain-containing protein, binds to Kir2.3 with a high affinity, causing the intracellular accumulation of Kir2.3 in cultured epithelial cells. However, the molecular basis of the TIP-1/Kir2.3 interaction is still poorly understood. Here, we present the crystal structure of TIP-1 in complex with the C-terminal Kir2.3-peptide (residues 436ȁ3;445) to reveal the molecular details of the interaction between them. Moreover, isothermal titration calorimetry experiments show that the C-terminal Kir2.3-peptide binds much more strongly to TIP-1 than to mammalian Lin-7, indicating that TIP-1 can compete with mammalian Lin-7 to uncouple Kir2.3 from its basolateral membrane anchoring complex. We further show that the phosphorylation/dephosphorylation of Ser443 within the C-terminal Kir2.3 PDZ-binding motif RRESAI dynamically regulates the Kir2.3/TIP-1 association in heterologous HEK293T cells. These data suggest that TIP-1 may act as an important regulator for the endocytic pathway of Kir2.3.