title: T-cadherin structures reveal a novel adhesive binding mechanism.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ciatto
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bahna
authors.forename: Niccolò
authors.initials: N
authors.lastname: Zampieri
authors.forename: Harper C
authors.initials: HC
authors.lastname: VanSteenhouse
authors.forename: Phini S
authors.initials: PS
authors.lastname: Katsamba
authors.forename: Goran
authors.initials: G
authors.lastname: Ahlsen
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Harrison
authors.forename: Julia
authors.initials: J
authors.lastname: Brasch
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Jin
authors.forename: Shoshana
authors.initials: S
authors.lastname: Posy
authors.forename: Jeremie
authors.initials: J
authors.lastname: Vendome
authors.forename: Barbara
authors.initials: B
authors.lastname: Ranscht
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Jessell
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D018360:Crystallography, X-Ray; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015820:Cadherins; C099972:H-cadherin; D002118:Calcium