@article{e6452fd865224805a0392e54d146e4a4,
title = "Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands",
abstract = "RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ligands but also co-receptors for activation, the mechanisms of which remain unclear due to lack of high-resolution structures of the ligand/co-receptor/receptor complexes. Here, we report cryo-EM structures of the extracellular region ternary complexes of GDF15/GFRAL/RET, GDNF/GFRa1/RET, NRTN/GFRa2/RET and ARTN/GFRa3/RET. These structures reveal that all the four ligand/co-receptor pairs, while using different atomic interactions, induce a specific dimerization mode of RET that is poised to bring the two kinase domains into close proximity for cross-phosphorylation. The NRTN/GFRa2/RET dimeric complex further pack into a tetrameric assembly, which is shown by our cell-based assays to regulate the endocytosis of RET. Our analyses therefore reveal both the common mechanism and diversification in the activation of RET by different ligands.",
author = "Jie Li and Guijun Shang and Chen, {Yu Ju} and Brautigam, {Chad A.} and Jen Liou and Xuewu Zhang and Bai, {Xiao Chen}",
note = "Funding Information: We thank Defen Lu, Tao Yue and Eunhee Choi for discussions and technical assistance. Single particle cryo-EM data were collected at the University of Texas Southwestern Medical Center (UTSW) Cryo-Electron Microscopy Facility that is funded by a Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Support Award (RP170644). We thank D Nicastro and D Stoddard for facility access and data acquisition. XB is supported in part by grants from CPRIT (RR160082) and the Welch foundation (I-1944–20180324). XZ is supported in part by grants from the National Institutes of Health (GM088197 and R35GM130289) and the Welch foundation (I-1702). XB and XZ are both Virginia Murchison Linthicum Scholars in Medical Research at UTSW. JLiou is supported by National Institutes of Health Grant GM113079. JLiou is a Sowell Family Scholar in Medical Research at UTSW. Funding Information: Cancer Prevention and Research Institute of Texas RR160082, Welch Foundation I-1944-20180324, National Institutes of Health GM088197, National Institutes of Health R35GM130289, Welch Foundation I-1702. Publisher Copyright: {\textcopyright} Li et al.",
year = "2019",
month = sep,
doi = "10.7554/eLife.47650.001",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}