Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, 72076 Tübingen, Germany.
Molecular and Cellular Anatomy, University of Regensburg, Universitätsstrasse 31, 93053 Regensburg, Germany.
Sci Signal. 2018 Feb 13;11(517):eaam9899. doi: 10.1126/scisignal.aam9899.
Polarity is a fundamental property of most cell types. The Par protein complex is a major driving force in generating asymmetrically localized protein networks and consists of atypical protein kinase C (aPKC), Par3, and Par6. Dysfunction of this complex causes developmental abnormalities and diseases such as cancer. We identified a PDZ domain-binding motif in Par6 that was essential for its interaction with Par3 in vitro and for Par3-mediated membrane localization of Par6 in cultured cells. In fly embryos, we observed that the PDZ domain-binding motif was functionally redundant with the PDZ domain in targeting Par6 to the cortex of epithelial cells. Our structural analyses by x-ray crystallography and NMR spectroscopy showed that both the PDZ1 and PDZ3 domains but not the PDZ2 domain in Par3 engaged in a canonical interaction with the PDZ domain-binding motif in Par6. Par3 thus has the potential to recruit two Par6 proteins simultaneously, which may facilitate the assembly of polarity protein networks through multivalent PDZ domain interactions.
极性是大多数细胞类型的基本特性。Par 蛋白复合物是产生不对称定位蛋白网络的主要驱动力，由非典型蛋白激酶 C(aPKC)、Par3 和 Par6 组成。该复合物的功能障碍会导致发育异常和疾病，如癌症。我们在 Par6 中鉴定出一个 PDZ 结构域结合基序，该基序对于其在体外与 Par3 的相互作用以及 Par3 介导的 Par6 在培养细胞中的膜定位是必需的。在果蝇胚胎中，我们观察到 PDZ 结构域结合基序在将 Par6 靶向上皮细胞皮层方面与 PDZ 结构域在功能上是冗余的。我们通过 X 射线晶体学和 NMR 光谱学的结构分析表明，Par3 的 PDZ1 和 PDZ3 结构域而不是 PDZ2 结构域与 Par6 的 PDZ 结构域结合基序发生了典型的相互作用。因此，Par3 有可能同时招募两个 Par6 蛋白，这可能通过多价 PDZ 结构域相互作用促进极性蛋白网络的组装。
