细胞生物学
GTP酶
生物
GTPase激活蛋白
支架蛋白
磷酸化
结构生物学
Rap1型
抗凋亡Ras信号级联
泛素
作者
Venkatesh Mysore,Zhi Wei Zhou,Chiara Ambrogio,Lianbo Li,Jonas N. Kapp,Chunya Lu,Qi Wang,Maxwell R. Tucker,Jeffrey J. Okoro,Gabriela Nagy-Davidescu,Xiao Chen Bai,Andreas Plückthun,Pasi A. Jänne,Kenneth D. Westover,Yibing Shan,David E. Shaw
标识
DOI:10.1038/s41594-021-00667-6
摘要
The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling.
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