Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions

Nat Commun. 2021 Apr 6;12(1):2070. doi: 10.1038/s41467-021-22080-9.


The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. Here, we report the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. We show that ectopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. We further demonstrate that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, our data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Cytoplasmic Vesicles / metabolism
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / metabolism*
  • Endocytosis
  • Imaginal Discs / cytology
  • Imaginal Discs / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Protein Binding
  • Protein Domains
  • Protein Interaction Mapping
  • Receptors, Tumor Necrosis Factor / metabolism*


  • Drosophila Proteins
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor
  • egr protein, Drosophila
  • grnd protein, Drosophila
  • wgn protein, Drosophila