The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism

Int J Mol Sci. 2021 Sep 28;22(19):10473. doi: 10.3390/ijms221910473.

Abstract

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell-cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph-ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph-Eph interfaces. One Eph-Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor-receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.

Keywords: Eph receptors; X-ray crystallography; fibronectin type III domain; kinase activation; ligand-binding domain; protein–protein interfaces; receptor clusters; receptor tyrosine kinases (RTKs).

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Mice
  • Protein Domains
  • Receptor, EphB2 / chemistry*
  • Receptor, EphB2 / genetics
  • Receptor, EphB2 / metabolism*
  • Signal Transduction*
  • Structure-Activity Relationship

Substances

  • Ephb2 protein, mouse
  • Receptor, EphB2