In cochlea, deafness-related protein PDZD7 is an indispensable component of the ankle link complex, which is critical for the maturation of inner-ear hair cell for sound perception. Ankle links, connecting the different rows of cochlear stereocilia, are essential for the staircase-like development of stereocilia. However, the molecular mechanism of how PDZD7 governs stereociliary development remains unknown. Here, we reported a novel PDZD7-binding partner, FCHSD2, identified by yeast two-hybrid screening. FCHSD2 was reported to be expressed in hair cell, where it co-operated with CDC42 and N-WASP to regulate the formation of cell protrusion. The association between FCHSD2 and PDZD7 was further confirmed in COS-7 cells. More importantly, we solved the complex structure of FCHSD2 tail with PDZD7 PDZ3 domain at 2.0 Å resolution. The crystal structure shows that PDZD7 PDZ3 adopts a typical PDZ domain topology, comprising five β strands and two α helixes. The PDZ-binding motif of FCHSD2 tail stretches through the αB/βB groove of PDZD7 PDZ3. Our study not only uncovers the interaction between FCHSD2 tail and PDZD7 PDZ3 at the atomic level, but also provides clues of connecting the ankle link complex with cytoskeleton dynamics for exploiting the molecular mechanism of stereociliary development.

中文翻译：

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耳聋相关蛋白 PDZD7 与 FCHSD2 的 C 末端尾形成复合物

在耳蜗中，耳聋相关蛋白 PDZD7 是踝关节复合体不可缺少的组成部分，对于内耳毛细胞的声音感知成熟至关重要。连接不同行的耳蜗纤毛的踝关节对纤毛的阶梯状发育至关重要。然而，PDZD7如何控制纤毛发育的分子机制仍然未知。在这里，我们报告了一种新的 PDZD7 结合伙伴 FCHSD2，通过酵母双杂交筛选鉴定。据报道，FCHSD2 在毛细胞中表达，它与 CDC42 和 N-WASP 合作调节细胞突起的形成。FCHSD2 和 PDZD7 之间的关联在 COS-7 细胞中得到进一步证实。更重要的是，我们以 2.0 Å 的分辨率用 PDZD7 PDZ3 结构域解决了 FCHSD2 尾部的复杂结构。晶体结构表明PDZD7 PDZ3采用典型的PDZ结构域拓扑结构，由5条β链和2条α螺旋组成。FCHSD2 尾部的 PDZ 结合基序延伸穿过 PDZD7 PDZ3 的 αB/βB 凹槽。我们的研究不仅揭示了 FCHSD2 tail 和 PDZD7 PDZ3 在原子水平上的相互作用，而且为探索纤毛发育的分子机制提供了将踝关节复合物与细胞骨架动力学联系起来的线索。