Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse

Cell. 2018 Apr 19;173(3):735-748.e15. doi: 10.1016/j.cell.2018.03.036.


Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large β barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a β propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the β propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.

Keywords: ADGRL1; adhesion GPCR; cryo-EM; embryogenesis; teneurin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing
  • Amino Acid Motifs
  • Animals
  • Axons
  • Bacterial Toxins / chemistry*
  • Cell Adhesion
  • Cell Line
  • Cyclic AMP / metabolism
  • Female
  • HEK293 Cells
  • Hormones / chemistry
  • Humans
  • Insecta
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Conformation
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Neuropeptides / chemistry
  • Protein Binding
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / chemistry
  • Signal Transduction
  • Synapses / metabolism*


  • Bacterial Toxins
  • Hormones
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • TENM2 protein, human
  • alpha-latrotoxin receptor
  • Cyclic AMP