6GL7

Neurturin-GFRa2-RET extracellular complex

Summary for 6GL7

• Entry DOI: 10.2210/pdb6gl7/pdb
• EMDB information: 0026
• Descriptor: Neurturin, GDNF family receptor alpha-2, Proto-oncogene tyrosine-protein kinase receptor Ret (3 entities in total)
• Functional Keywords: neurotrophic signalling, receptor tyrosine kinase, gdnf family of ligands, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 255986.77

Authors

Bigalke, J.M.,Aibara, S.,Sandmark, J.,Amunts, A. (deposition date: 2018-05-23, release date: 2019-08-14, Last modification date: 2019-12-18)

Primary citation

Bigalke, J.M.,Aibara, S.,Roth, R.,Dahl, G.,Gordon, E.,Dorbeus, S.,Amunts, A.,Sandmark, J.
Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain.
Sci Adv, 5:eaau4202-eaau4202, 2019

PubMed Abstract: Signaling 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 GFRα2 and determined its structure at 5.7-Å resolution by cryo-EM. The proteins form an assembly through RET-GFRα2 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 GFRα2 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.

PubMed: 31392261
DOI: 10.1126/sciadv.aau4202

Experimental method

ELECTRON MICROSCOPY (6.3 Å)