Lateral self‐assembly of E‐cadherin directed by cooperative calcium binding

Alattia, Jean‐René; Ames, James B.; Porumb, Tudor; Tong, Kit I.; Heng, Y. M.; Ottensmeyer, Peter; Kay, Cyril M.; Ikura, Mitsuhiko

doi:10.1016/s0014-5793(97)01333-1

Cited by 72 publications

(57 citation statements)

References 16 publications

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“…Furthermore, measurements suggest that the binding of Ca 2 þ to the EC linkers has a positive cooperativity; various Hill coefficients ranging up to 3.7 have been reported in the literature [20][21][22][23]37 . Owing to wide variations in the measured affinity of the ectodomain for Ca 2 þ ions, we tested the force-dependent binding kinetics of X-dimers at Ca 2 þ concentrations ranging from 1.5 mM to 300 mM; studies show that the cadherin ectodomain stiffens and adopt an extended trans-dimer conformation at solution Ca 2 þ concentrations of 1 mM (refs 14,22).…”

Section: Article Nature Communications | Doi: 101038/ncomms4941mentioning

confidence: 98%

“…Different solution Ca 2 þ concentrations were simulated by varying the number of Ca 2 þ ions bound to the linker between the EC1 and EC2 domains. Since each EC1-2 linker binds cooperatively to three Ca 2 þ ions [20][21][22][23] , physiological Ca 2 þ concentrations were simulated by binding six Ca 2 þ ions to the X-dimer. Lower solution Ca 2 þ concentrations were simulated by eliminating one, two or all three Ca 2 þ ions from each linker in the X-dimer.…”

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confidence: 99%

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Resolving the molecular mechanism of cadherin catch bond formation

et al. 2014

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Classical cadherin Ca 2 þ -dependent cell-cell adhesion proteins play key roles in embryogenesis and in maintaining tissue integrity. Cadherins mediate robust adhesion by binding in multiple conformations. One of these adhesive states, called an X-dimer, forms catch bonds that strengthen and become longer lived in the presence of mechanical force. Here we use single-molecule force-clamp spectroscopy with an atomic force microscope along with molecular dynamics and steered molecular dynamics simulations to resolve the molecular mechanisms underlying catch bond formation and the role of Ca 2 þ ions in this process. Our data suggest that tensile force bends the cadherin extracellular region such that they form long-lived, force-induced hydrogen bonds that lock X-dimers into tighter contact. When Ca 2 þ concentration is decreased, fewer de novo hydrogen bonds are formed and catch bond formation is eliminated.

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Section: Article Nature Communications | Doi: 101038/ncomms4941mentioning

confidence: 98%

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confidence: 99%

Resolving the molecular mechanism of cadherin catch bond formation

et al. 2014

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“…This result reflects the behavior of cadherins expressed at the cell surface and is in agreement with studies done on various cadherin-derived recombinant fragments. Indeed, except for the earliest works of Shapiro et al (14) and Brieher et al (34), multimers of cadherins were formed only in the presence of Ca 2ϩ (20,(23)(24)(25)35). Cryoelectron microscopy allows us to visualize the hexameric structures as elongated cigar-shaped particles.…”

Section: Electron Microscopy Of Ve-ec1-4 -In the Presence Of 5 MM Camentioning

confidence: 99%

Self-assembly of the Vascular Endothelial Cadherin Ectodomain in a Ca2+-dependent Hexameric Structure

Legrand¹,

Bibert²,

Jaquinod³

et al. 2001

Journal of Biological Chemistry

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Vascular endothelial cadherin (VE-cadherin) is a transmembrane protein essential for endothelial cell monolayer integrity (Gulino, D., Delachanal, E., Concord, E., Genoux, Y., Morand, B., Valiron, M. O., Sulpice, E., Scaife, R., Alemany, M., and Vernet, T. (1998) J. Biol. Chem. 273, 29786 -29793). This molecule belongs to the cadherin family of cell-cell adhesion receptors, for which molecular details of homotypic interactions are still lacking. In this study, a recombinant fragment encompassing the four N-terminal modules of VE-cadherin (VE-EC1-4) was shown to associate, in solution, as a stable Ca 2؉ -dependent oligomeric structure. Cross-linking experiments combined with mass spectrometry demonstrated that this oligomer is a hexamer. Gel filtration chromatography experiments and analytical ultracentrifugation analyses revealed the existence of an equilibrium between the hexameric and monomeric species of VE-EC1-4. The concentration at which 50% of VE-EC1-4 is in its hexameric form was estimated as 1 M. The dimensions of the hexamer, measured by cryoelectron microscopy to be 233 ؎ 10 ؋ 77 ؎ 7 Å, are comparable to the thickness of adherens endothelial cell-cell junctions. Altogether, the results allow us to propose a novel homotypic interaction model for the class II VEcadherin, in which six molecules of cadherin form a hexamer.

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“…In a previous site-directed mutagenesis experiment, one aspartate (amino acid 134, underlined) in the calcium binding motif DAD of mouse E-cadherin was changed to alanine which led to a complete loss of calcium-dependent aggregation (Ozawa et al, 1990a). Dimerization of E-cadherin has also been shown to be Ca 2+ -induced (Alattia et al, 1997). Defective processing of mutated E-cadherin proteins could also lead to decrease or loss of aggregation because cells expressing unprocessed E-cadherin show no intercellular adhesion (Ozawa and Kemler, 1990).…”

Section: +mentioning

confidence: 99%

Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility

Handschuh¹,

Candidus

Luber³

et al. 1999

Oncogene

189

137

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A major function of the cell-to-cell adhesion molecule Ecadherin is the maintenance of cell adhesion and tissue integrity. E-cadherin de®ciency in tumours leads to changes in cell morphology and motility, so that Ecadherin is considered to be a suppressor of invasion. In this study we investigated the functional consequences of three tumour-associated gene mutations that aect the extracellular portion of E-cadherin: in-frame deletions of exons 8 or 9 and a point mutation in exon 8, as they were found in human gastric carcinomas. Human MDA-MB-435S breast carcinoma cells and mouse L ®broblasts were stably transfected with the wild-type and mutant cDNAs, and the resulting changes in localization of E-cadherin, cell morphology, strength of calcium-dependent aggregation as well as cell motility and actin cytoskeleton organization were studied. We found that cells transfected with wild-type E-cadherin showed an epitheloid morphology, while all cell lines expressing mutant E-cadherin exhibited more irregular cell shapes. Cells expressing Ecadherin mutated in exon 8 showed the most scattered appearance, whereas cells with deletion of exon 9 had an intermediate state. Mutant E-cadherins were localized to the lateral regions of cell-to-cell contact sites. Additionally, both exon 8-mutated E-cadherins showed apical and perinuclear localization, and actin ®laments were drastically reduced. MDA-MB-435S cells with initial calciumdependent cell aggregation exhibited decreased aggregation and, remarkably, increased cell motility, when mutant E-cadherin was expressed. Therefore, we conclude that these E-cadherin mutations may not simply aect cell adhesion but may act in a trans-dominant-active manner, i.e. lead to increased cell motility. Our study suggests that E-cadherin mutations aecting exons 8 or 9 are the cause of multiple morphological and functional disorders and could induce the scattered morphology and the invasive behaviour of diuse type-gastric carcinomas.

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Lateral self‐assembly of E‐cadherin directed by cooperative calcium binding

Cited by 72 publications

References 16 publications

Resolving the molecular mechanism of cadherin catch bond formation

Resolving the molecular mechanism of cadherin catch bond formation

Self-assembly of the Vascular Endothelial Cadherin Ectodomain in a Ca2+-dependent Hexameric Structure

Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility

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