PDZ domains are modular domains that conventionally bind to C terminal or internal motifs of target proteins to control cellular functions through the regulation of protein complex assemblies. Almost all reported structures of PDZ-target protein complexes rely on fragments or peptides as target proteins. No intact target protein complexed with PDZ was structurally characterized. In this study, we used NMR spectroscopy and other biochemistry and biophysics tools to uncover insights into structural coupling between the PDZ domain of protein interacting with C-kinase 1 (PICK1) and α7 nicotinic acetylcholine receptors (α7 nAChR). Notably, the intracellular domains of both α7 nAChR and PICK1 PDZ exhibit a high degree of plasticity in their coupling. Specifically, the MA helix of α7 nAChR interacts with residues lining the canonical binding site of the PICK1 PDZ, while flexible loops also engage in protein–protein interactions. Both hydrophobic and electrostatic interactions mediate the coupling. Overall, the resulting structure of the α7 nAChR-PICK1 complex reveals an unconventional PDZ binding mode, significantly expanding the repertoire of functionally important PDZ interactions.

中文翻译：

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α7 nAChR-PICK1 复合物中揭示的非常规 PDZ 识别


PDZ 结构域是模块化结构域，通常与目标蛋白的 C 末端或内部基序结合，通过调节蛋白复合物组装来控制细胞功能。几乎所有报道的 PDZ-靶蛋白复合物结构都依赖于片段或肽作为靶蛋白。未对与 PDZ 复合的完整靶蛋白进行结构表征。在这项研究中，我们使用核磁共振波谱和其他生物化学和生物物理学工具来揭示与 C 激酶 1 (PICK1) 相互作用的蛋白质的 PDZ 结构域和 α7 烟碱乙酰胆碱受体 (α7 nAChR) 之间的结构耦合。值得注意的是，α7 nAChR 和 PICK1 PDZ 的胞内结构域在耦合中表现出高度的可塑性。具体来说，α7 nAChR 的 MA 螺旋与 PICK1 PDZ 经典结合位点内衬的残基相互作用，而柔性环也参与蛋白质-蛋白质相互作用。疏水性和静电相互作用都介导耦合。总的来说，α7 nAChR-PICK1 复合物的结构揭示了一种非常规的 PDZ 结合模式，显着扩展了功能上重要的 PDZ 相互作用的范围。