Structure and binding mechanism of vascular endothelial cadherin: a divergent classical cadherin.
Vascular endothelial cadherin (VE-cadherin), a divergent member of the type II classical cadherin family of cell adhesion proteins, mediates homophilic adhesion in the vascular endothelium. Previous investigations with a bacterially produced protein suggested that VE-cadherin forms cell surface trimers that bind between apposed cells to form hexamers. Here we report studies of mammalian-produced VE-cadherin ectodomains suggesting that, like other classical cadherins, VE-cadherin forms adhesive trans dimers between monomers located on opposing cell surfaces. Trimerization of the bacterially produced protein appears to be an artifact that arises from a lack of glycosylation. We also present the 2.1-Å-resolution crystal structure of the VE-cadherin EC1-2 adhesive region, which reveals homodimerization via the strand-swap mechanism common to classical cadherins. In common with type II cadherins, strand-swap binding involves two tryptophan anchor residues, but the adhesive interface resembles type I cadherins in that VE-cadherin does not form a large nonswapped hydrophobic surface. Thus, VE-cadherin is an outlier among classical cadherins, with characteristics of both type I and type II subfamilies.
Department of Biochemistry and Molecular Biophysics, Columbia University, 701 West 168th Street, New York, NY 10032, USA.
Julia
J
Brasch
Oliver J
OJ
Harrison
Goran
G
Ahlsen
Stewart M
SM
Carnally
Robert M
RM
Henderson
Barry
B
Honig
Lawrence
L
Shapiro
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D004730:Endothelium, Vascular / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017386:Sequence Homology, Amino Acid; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5
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