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.
复制标题
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：
10.1016/j.celrep.2021.109834
复制
发表时间：
2021-10-19
期刊：
影响因子：
8.8
通讯作者：
Lemmon MA
中科院分区：
文献类型：
--
作者：
Shi F;Mendrola JM;Sheetz JB;Wu N;Sommer A;Speer KF;Noordermeer JN;Kan ZY;Perry K;Englander SW;Stayrook SE;Fradkin LG;Lemmon MA
WNTs在发育和疾病中发挥关键作用，通过Frizzled七通道跨膜受体和包括ROR和RYK家族受体酪氨酸激酶(RTK)在内的众多辅助受体传递信号。我们描述了果蝇ROR和RYK同源物NRK(神经特异性受体酪氨酸激酶)和DERILED-2(DRL-2)胞外区的晶体结构和WNT结合特性，它们分别通过FZD相关的半胱氨酸富含结构域(CRD)和WNT抑制因子(WIF)结构域与WNT结合。我们的晶体结构表明，NRK和DRL-2都不能容纳通常连接到WNTs上的酰基链。NRK CRD含有一种埋得很深的结合脂肪酸，不太可能被交换。DRL-2的WIF结构域缺乏WIF-1中的脂质结合部位。我们还发现，重组的DWNT-5可以结合果蝇的ROR和RYK同源物，尽管缺乏酰基链。除了对WNT/受体相互作用位点的分析外，我们的结构还为WNT如何将RTK辅助受体招募到信号复合体中提供了进一步的见解。
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 the Drosophila ROR 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 bind Drosophila ROR 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.
登录
查看更多内容
影响因子：
64.8
作者：
Bonkowsky, JL;Yoshikawa, S;Thomas, JB
通讯作者：
Thomas, JB
影响因子：
2.7
作者：
Fradkin, LG;van Schie, M;Noordermeer, JN
通讯作者：
Noordermeer, JN
影响因子：
4.8
作者：
Bourhis, Eric;Tam, Christine;Hannoush, Rami N.
通讯作者：
Hannoush, Rami N.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH