ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes
ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes
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ROR 和 RYK 胞外区结构表明受体酪氨酸激酶具有不同的 WNT 识别模式
DOI：
10.1101/2021.04.29.442059
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Lemmon1, 2
中科院分区：
文献类型：
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作者：
Fumin Shi1, 2;Lemmon1, 2
WNTs在发育和疾病中发挥关键作用，通过卷曲（FZD）七通跨膜受体和许多共受体，包括ROR和RYK家族受体酪氨酸激酶（RTKs）发出信号。我们描述了果蝇aror和RYK同源基因Nrk（神经特异性受体酪氨酸激酶）和derail -2 （Drl-2）细胞外区域的晶体结构和wnt结合特征，它们分别通过fzd相关的富含半胱氨酸结构域（CRD）和wnt抑制因子（WIF）结构域结合wnt。我们的晶体结构表明Nrk和Drl-2都不能容纳通常附着在wnt上的酰基链。Nrk CRD含有一种深埋的结合脂肪酸，不太可能被交换。Drl-2 WIF结构域缺乏WIF-1中的脂质结合位点。我们还发现重组DWnt-5可以结合果蝇的or和RYK同源物，尽管缺乏一个酰基链。除了对WNT/受体相互作用位点的分析外，我们的结构还进一步深入了解了WNT如何将RTK共受体招募到信号复合物中。
WNTs play key roles in development and disease, signaling through Frizzled (FZD) seven-pass transmembrane receptors and numerous co-receptors including ROR and RYK family receptor tyrosine kinases (RTKs). We describe crystal structures and WNT-binding characteristics of extracellular regions from theDrosophilaROR and RYK orthologs Nrk (neurospecific receptor tyrosine kinase) and Derailed-2 (Drl-2), which bind WNTs though a FZD-related cysteine-rich domain (CRD) and WNT-inhibitory factor (WIF) domain respectively. Our crystal structures suggest that neither Nrk nor Drl-2 can accommodate the acyl chain typically attached to WNTs. The Nrk CRD contains a deeply buried bound fatty acid, unlikely to be exchangeable. The Drl-2 WIF domain lacks the lipid-binding site seen in WIF-1. We also find that recombinant DWnt-5 can bindDrosophilaROR and RYK orthologs despite lacking an acyl chain. Alongside analyses of WNT/receptor interaction sites, our structures provide further insight into how WNTs may recruit RTK co-receptors into signaling complexes.