T-cadherin structures reveal a novel adhesive binding mechanism


  • C. Ciatto
  • F. Bahna
  • N. Zampieri
  • H.C. VanSteenhouse
  • P.S. Katsamba
  • G. Ahlsen
  • O.J. Harrison
  • J. Brasch
  • X. Jin
  • S. Posy
  • J. Vendome
  • B. Ranscht
  • T.M. Jessell
  • B. Honig
  • L. Shapiro


  • Nature Structural & Molecular Biology


  • Nat Struct Mol Biol 17 (3): 339-347


  • Vertebrate genomes encode 19 classical cadherins and about 100 nonclassical cadherins. Adhesion by classical cadherins depends on binding interactions in their N-terminal EC1 domains, which swap N-terminal beta-strands between partner molecules from apposing cells. However, strand-swapping sequence signatures are absent from nonclassical cadherins, raising the question of how these proteins function in adhesion. Here, we show that T-cadherin, a glycosylphosphatidylinositol (GPI)-anchored cadherin, forms dimers through an alternative nonswapped interface near the EC1-EC2 calcium-binding sites. Mutations within this interface ablate the adhesive capacity of T-cadherin. These nonadhesive T-cadherin mutants also lose the ability to regulate neurite outgrowth from T-cadherin-expressing neurons. Our findings reveal the likely molecular architecture of the T-cadherin homophilic interface and its requirement for axon outgrowth regulation. The adhesive binding mode used by T-cadherin may also be used by other nonclassical cadherins.