title: Structural basis of calcium-induced E-cadherin rigidification and dimerization.
abstract: The cadherins mediate cell adhesion and play a fundamental role in normal development. They participate in the maintenance of proper cell-cell contacts: for example, reduced levels of epithelial cadherin (E-cadherin) correlate with increased invasiveness in many human tumour cell types. The cadherins typically consist of five tandemly repeated extracellular domains, a single membrane-spanning segment and a cytoplasmic region. The N-terminal extracellular domains mediate cell-cell contact while the cytoplasmic region interacts with the cytoskeleton through the catenins. Cadherins depend on calcium for their function: removal of calcium abolishes adhesive activity, renders cadherins vulnerable to proteases (reviewed in ref. 4) and, in E-cadherin, induces a dramatic reversible conformational change in the entire extracellular region. We report here the X-ray crystal structure at 2.0 A resolution of the two N-terminal extracellular domains of E-cadherin in the presence of calcium. The structure reveals a two-fold symmetric dimer, each molecule of which binds a contiguous array of three bridged calcium ions. Not only do the bound calcium ions linearize and rigidify the molecule, they promote dimerization. Although the N-terminal domain of each molecule in the dimer is aligned in a parallel orientation, the interactions between them differ significantly from those found in the neural cadherin (N-cadherin) N-terminal domain (NCD1) structure. The E-cadherin dual-domain structure reported here defines the role played by calcium in the cadherin-mediated formation and maintenance of solid tissues.
authors.affiliation: Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Nagar
authors.forename: M
authors.initials: M
authors.lastname: Overduin
authors.forename: M
authors.initials: M
authors.lastname: Ikura
authors.forename: J M
authors.initials: JM
authors.lastname: Rini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001704:Biopolymers; D015820:Cadherins / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001704:Biopolymers; D015820:Cadherins; D011994:Recombinant Proteins; D002118:Calcium