Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain

Sci Adv. 2019 Jul 31;5(7):eaau4202. doi: 10.1126/sciadv.aau4202. eCollection 2019 Jul.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Cysteine / chemistry
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / chemistry*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / ultrastructure
  • Humans
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / ultrastructure
  • Neurturin / chemistry*
  • Neurturin / ultrastructure
  • Protein Binding / genetics
  • Protein Conformation*
  • Protein Domains / genetics
  • Proto-Oncogene Proteins c-ret / chemistry*
  • Proto-Oncogene Proteins c-ret / ultrastructure
  • Signal Transduction


  • GFRA2 protein, human
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Multiprotein Complexes
  • NRTN protein, human
  • Neurturin
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Cysteine