受体酪氨酸激酶ROR2介导非规范的WNT5A信号,以协调组织形态发生过程,通路的功能障碍导致Robinow综合征,短指B和转移性疾病。ROR2功能所需的域和机制,然而,仍然不清楚。我们解决了ROR2的细胞外富含半胱氨酸(CRD)和Kringle(Kr)结构域的晶体结构,与其他CRD不同,ROR2CRD缺乏结合脂质/脂质修饰蛋白的特征疏水口袋,例如WNTs,提出了一种新的配体接收机制。功能上,我们显示了ROR2CRD,但不是其他领域,是必需的,并且最低限度地足以促进WNT5A信令,CRD和邻近Kr中的Robinow突变会损害ROR2的分泌和功能。此外,使用针对WNT受体的卷曲(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起作用以增强包括FZ的受体超复合物的功能以转导WNT5A信号。
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.