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.
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The structures of E-cadherin and N-cadherin have been determined to a resolution of 2 Å by x-ray crystallography.
“The structures of these cadherins have been determined to a resolution of 2 A ˚´by x-ray crystallography [45].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [45]
The paper's findings are strengthened by the fact that the results of modeling of cadherin-cadherin interactions were very similar to what has been found by x-ray crystallography.
“However, our findings are strengthened by the fact that the results of our modeling of cadherin-cadherin interactions were very similar to what has been found by xray crystallography [45].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [45]
Visually, E-cadherin redocking was virtually indistinguishable from the reported crystal structure.
“Visually, E-cadherin redocking was virtually indistinguishable from that of the reported structure determined by crystallography [45].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [45]
Cadherins regulate calcium-dependent cell-cell adherent junctions, where chelation of calcium abolishes adhesive activity and allows proteolytic degradation of cadherins.
“Cadherins regulate calcium-dependent cell–cell adherent junctions, where the chelation of calcium abolishes adhesive activity and allows proteolytic degradation of cadherins (Nagar and Overduint, 1996; Kim et al., 2011).”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Nagar and Overduint, 1996
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Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells
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- Authors
- Nagar, B., Overduin, M., Ikura, M., & Rini, J. M.
- Affiliations
- University of Toronto (CA)
- University of Tsukuba (JP)
- Venue
- Nature
- Published
- 1996-03
- Volume
- 380
- Issue
- 6572
- Pages
- 360-364
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2035323213
- Cited by
- 684
- References
- 24
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 11 · 2023: 14 · 2022: 20 · 2021: 15 · 2020: 17 · 2019: 16 · 2018: 17 · 2017: 15 · 2016: 16 · 2015: 13 · 2014: 26 · 2013: 16 · 2012: 30
- FWCI
- 16.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- E-cadherin, calcium binding, extracellular domain, protein dimerization, crystal structure, cell adhesion, catenins, tumour invasiveness
- MeSH terms
- Amino Acid Sequence, Animals, Biopolymers, Calcium, Escherichia coli, Models, Molecular, Molecular Sequence Data, Protein Conformation, Recombinant Proteins, Structure-Activity Relationship, Cadherins, Crystallography, X-Ray, Mice
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