Structural highlights
Disease
NRTN_HUMAN Hirschsprung disease. Genetic variations in NRTN may contribute to Hirschsprung disease, in association with mutations of RET gene, and possibly mutations in other loci. Hirschsprung disease is a disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.[1]
Function
NRTN_HUMAN Supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Might control the size of non-neuronal cell population such as haemopoietic cells.
Publication Abstract from PubMed
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/GFRalpha1/RET, NRTN/GFRalpha2/RET and ARTN/GFRalpha3/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/GFRalpha2/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.
Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands.,Li J, Shang G, Chen YJ, Brautigam CA, Liou J, Zhang X, Bai XC Elife. 2019 Sep 19;8. pii: 47650. doi: 10.7554/eLife.47650. PMID:31535977[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attie T, Bachy B, Munnich A, Lyonnet S. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998 Sep;7(9):1449-52. PMID:9700200
- ↑ Li J, Shang G, Chen YJ, Brautigam CA, Liou J, Zhang X, Bai XC. Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. Elife. 2019 Sep 19;8. pii: 47650. doi: 10.7554/eLife.47650. PMID:31535977 doi:http://dx.doi.org/10.7554/eLife.47650
