T-cadherin structures reveal a novel adhesive binding mechanism.
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.
Ciatto
Carlo
C
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
Bahna
Fabiana
F
Zampieri
Niccolò
N
VanSteenhouse
Harper C
HC
Katsamba
Phini S
PS
Ahlsen
Goran
G
Harrison
Oliver J
OJ
Brasch
Julia
J
Jin
Xiangshu
X
Posy
Shoshana
S
Vendome
Jeremie
J
Ranscht
Barbara
B
Jessell
Thomas M
TM
Honig
Barry
B
Shapiro
Lawrence
L
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
D015820:Cadherins; C099972:H-cadherin; D002118:Calcium