State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, D-22607 Hamburg, Germany.
Neuron. 2018 Mar 21;97(6):1261-1267.e4. doi: 10.1016/j.neuron.2018.02.010. Epub 2018 Mar 1.
Axon guidance involves the spatiotemporal interplay between guidance cues and membrane-bound cell-surface receptors, present on the growth cone of the axon. Netrin-1 is a prototypical guidance cue that binds to deleted in colorectal cancer (DCC), and it has been proposed that the guidance cue Draxin modulates this interaction. Here, we present structural snapshots of Draxin/DCC and Draxin/Netrin-1 complexes, revealing a triangular relationship that affects Netrin-mediated haptotaxis and fasciculation. Draxin interacts with DCC through the N-terminal four immunoglobulin domains, and Netrin-1 through the EGF-3 domain, in the same region where DCC binds. Netrin-1 and DCC bind to adjacent sites on Draxin, which appears to capture Netrin-1 and tether it to the DCC receptor. We propose the conformational flexibility of the single-pass membrane receptor DCC is used to promote fasciculation and regulate axon guidance through concerted Netrin-1/Draxin binding. VIDEO ABSTRACT.
轴突导向涉及导向线索和膜结合细胞表面受体之间的时空相互作用，这些受体存在于轴突的生长锥上。神经导向因子 1 是一种典型的导向线索，它与结直肠肿瘤缺失蛋白（DCC）结合，有人提出导向线索 Draxin 调节这种相互作用。在这里，我们呈现了 Draxin/DCC 和 Draxin/神经导向因子 1 复合物的结构快照，揭示了一种影响神经导向因子介导的趋化性和成束的三角关系。Draxin 通过免疫球蛋白结构域 N 端的四个结构域与 DCC 相互作用，通过 EGF-3 结构域与 Netrin-1 相互作用，该区域是 DCC 结合的区域。神经导向因子 1 和 DCC 结合在 Draxin 的相邻位点上，这似乎捕获了神经导向因子 1 并将其系在 DCC 受体上。我们提出，单次跨膜受体 DCC 的构象灵活性被用来促进成束，并通过协调的神经导向因子 1/Draxin 结合来调节轴突导向。视频摘要。
