Structures and pH-dependent dimerization of the Sevenless receptor tyrosine kinase. Cerutti et al.

Sevenless (Sev) is a Drosophila receptor tyrosine kinase (RTK) required for the specification of the R7 photoreceptor. It is cleaved into alpha and beta subunits and binds the ectodomain of the G-protein coupled receptor Bride of Sevenless (Boss). Previous work showed that the Boss ectodomain could bind but not activate Sev; rather, the whole seven-pass transmembrane Boss was required. Here we show that Sev does not need to be cleaved to function, and that a single-pass transmembrane form of Boss activates Sev. We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss implications in the process of Sev activation. The Sev human homolog, Receptor Oncogene from Sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.

七少（Sevenless, Sev）是果蝇（Drosophila）中参与R7光感受器细胞发育特化的受体酪氨酸激酶（receptor tyrosine kinase, RTK）。该蛋白可被切割为α与β两个亚基，并结合G蛋白偶联受体（G-protein coupled receptor）“无翅配偶体（Bride of Sevenless, Boss）”的胞外域。既往研究显示，Boss的胞外域虽可与Sev结合，但无法激活其信号通路；完整的七次跨膜Boss蛋白才是激活Sev的必要条件。本研究证实，Sev无需经过切割即可发挥功能，且单次跨膜形式的Boss即可激活Sev。我们通过冷冻电子显微镜术（cryo-electron microscopy）与生物物理方法，解析了Sev的配体结合与pH依赖性二聚化的结构基础，并探讨了其在Sev激活过程中的相关机制。此外，Sev的人类同源蛋白——肉瘤1受体癌基因（Receptor Oncogene from Sarcoma 1, ROS1）与致癌性转化密切相关，本文还将讨论二者的结构相似性。