Structure and binding mechanism of vascular endothelial cadherin: a divergent classical cadherin |
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Authors: | Brasch Julia Harrison Oliver J Ahlsen Goran Carnally Stewart M Henderson Robert M Honig Barry Shapiro Lawrence |
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Affiliation: | 1 Department of Biochemistry and Molecular Biophysics, Columbia University, 701 West 168th Street, New York, NY 10032, USA2 Howard Hughes Medical Institute, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA3 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK4 Center for Computational Biology and Bioinformatics, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA5 Edward S. Harkness Eye Institute, Columbia University in the City of New York, 635 West 165th Street, New York, NY 10032, USA |
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Abstract: | 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. |
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Keywords: | VE-cadherin, vascular endothelial cadherin EC, extracellular cadherin BSA, buried surface area N-cadherin, neural cadherin EM, electron microscopy HEK, human embryonal kidney GNTI, N-acetyl-glucosaminyl transferase I AUC, analytical ultracentrifugation E-cadherin, epithelial cadherin C-cadherin, Xenopus cleavage stage cadherin AFM, atomic force microscopy PDB, Protein Data Bank |
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