6q2n
Cryo-EM structure of RET/GFRa1/GDNF extracellular complex
Structural highlights
DiseaseGDNF_HUMAN Defects in GDNF may be a cause of Hirschsprung disease type 3 (HSCR3) [MIM:613711. In association with mutations of RET gene, defects in GDNF may be involved in Hirschsprung disease. This genetic disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.[1] [2] [3] [4] Defects in GDNF are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.[5] FunctionGDNF_HUMAN Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.[6] Publication Abstract from PubMedRET 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[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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