The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.

中文翻译：

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脊椎动物非经典 WNT5A 信号传导中 ROR2 富含半胱氨酸结构域的结构和功能

受体酪氨酸激酶 ROR2 介导非经典 WNT5A 信号传导以协调组织形态发生过程，该通路的功能障碍会导致 Robinow 综合征、短指 B 型和转移性疾病。然而，ROR2 功能所需的结构域和机制仍不清楚。我们解析了 ROR2 的胞外富含半胱氨酸 (CRD) 和 Kringle (Kr) 结构域的晶体结构，发现与其他 CRD 不同，ROR2 CRD 缺乏结合脂质/脂质修饰蛋白（例如 WNT）的标志性疏水口袋，提出了一种新的配体接收机制。从功能上讲，我们发现 ROR2 CRD（而不是其他结构域）是促进 WNT5A 信号传导所必需的，并且至少足以促进 WNT5A 信号传导，并且 CRD 和相邻 Kr 中的 Robinow 突变会损害 ROR2 的分泌和功能。此外，使用针对 WNT 受体卷曲 (FZ) 家族的功能激活和干扰抗体，我们证明了 FZ 参与 WNT5A-ROR 信号传导。因此，ROR2 通过其 CRD 发挥作用，增强包括 FZ 在内的受体超级复合物的功能，以转导 WNT5A 信号。