Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins

Cell Rep. 2020 Feb 25;30(8):2655-2671.e7. doi: 10.1016/j.celrep.2020.02.003.


Non-clustered δ1- and δ2-protocadherins, close relatives of clustered protocadherins, function in cell adhesion and motility and play essential roles in neural patterning. To understand the molecular interactions underlying these functions, we used solution biophysics to characterize binding of δ1- and δ2-protocadherins, determined crystal structures of ectodomain complexes from each family, and assessed ectodomain assembly in reconstituted intermembrane junctions by cryoelectron tomography (cryo-ET). Homophilic trans (cell-cell) interactions were preferred for all δ-protocadherins, with additional weaker heterophilic interactions observed exclusively within each subfamily. As expected, δ1- and δ2-protocadherin trans dimers formed through antiparallel EC1-EC4 interfaces, like clustered protocadherins. However, no ectodomain-mediated cis (same-cell) interactions were detectable in solution; consistent with this, cryo-ET of reconstituted junctions revealed dense assemblies lacking the characteristic order observed for clustered protocadherins. Our results define non-clustered protocadherin binding properties and their structural basis, providing a foundation for interpreting their functional roles in neural patterning.

Keywords: X-ray crystallography; cadherin; cell adhesion; cryo-electron tomography; homophilic adhesion; neuronal cell adhesion; non-clustered protocadherins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biophysical Phenomena*
  • Cadherins / chemistry*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Conserved Sequence
  • Female
  • HEK293 Cells
  • Humans
  • Kinetics
  • Liposomes
  • Models, Molecular
  • Mutation / genetics
  • Protein Binding
  • Protein Domains
  • Protein Multimerization
  • Solutions
  • Structure-Activity Relationship
  • Surface Plasmon Resonance
  • Xenopus


  • Cadherins
  • Liposomes
  • Solutions