Sugi Takuma, Oyama Takuji, Morikawa Kosuke, Jingami Hisato
Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.
Biochem Biophys Res Commun. 2008 Feb 8;366(2):373-8. doi: 10.1016/j.bbrc.2007.11.138. Epub 2007 Dec 4.
Lipid-mediated regulatory mechanism of the C-terminal ligand binding to PDZ domains is not fully understood, despite their roles in subcellular organization. Here, we provide structural insights into the phosphatidylinositol 4,5-bisphosphate (PIP(2)) recognition mode of a PDZ domain, as revealed from the crystal structure of the phosphate-bound PDZ domain. Two adjacent phosphate ions bind to the basic residues close to the amino terminus of the alpha2 helix in the Tamalin PDZ domain, reflecting an interaction mode of the two phosphate groups of PIP(2). Based on the observed location of the two phosphate molecules within the PDZ domain, we built the docking model of PIP(2) with the PDZ domain of the well-known PIP(2)-binding protein, syntenin-1. This model suggests that the hydrophobic diacylglycerol group of PIP(2) could contact the ligand-binding groove of the PDZ domain. These structural features well explain biological phenomena, which were previously reported for the PIP(2)-mediated PDZ ligand-binding regulation.
尽管脂质介导的C末端配体与PDZ结构域结合的调节机制在亚细胞组织中发挥作用，但其尚未完全被理解。在这里，我们通过磷酸结合的PDZ结构域的晶体结构，揭示了PDZ结构域对磷脂酰肌醇4,5 - 二磷酸（PIP(2)）的识别模式的结构见解。两个相邻的磷酸离子与Tamalin PDZ结构域中α2螺旋氨基末端附近的碱性残基结合，反映了PIP(2)的两个磷酸基团的相互作用模式。基于在PDZ结构域内观察到的两个磷酸分子的位置，我们构建了PIP(2)与著名的PIP(2)结合蛋白syntenin-1的PDZ结构域的对接模型。该模型表明，PIP(2)的疏水二酰基甘油基团可以与PDZ结构域的配体结合凹槽接触。这些结构特征很好地解释了先前报道的PIP(2)介导的PDZ配体结合调节的生物学现象。
