6gl7
Neurturin-GFRa2-RET extracellular complex
Structural highlights
DiseaseNRTN_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] FunctionNRTN_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 PubMedSignaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRalpha2 and determined its structure at 5.7-A resolution by cryo-EM. The proteins form an assembly through RET-GFRalpha2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFRalpha2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases. Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain.,Bigalke JM, Aibara S, Roth R, Dahl G, Gordon E, Dorbeus S, Amunts A, Sandmark J Sci Adv. 2019 Jul 31;5(7):eaau4202. doi: 10.1126/sciadv.aau4202. eCollection 2019, Jul. PMID:31392261[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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