Cadherin adhesion depends on a salt bridge at the N-terminus

Harrison, O.J.; Corps, Elaine M.; Kilshaw, Peter J.

doi:10.1242/jcs.02539

Cited by 40 publications

(41 citation statements)

References 42 publications

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“…It has been shown that strand-exchange during cadherin dimer formation depends on the formation of an intermolecular salt bridge between the N-terminal amino group and the side chain of Glu-89 (41). An equivalent glutamic acid is found at position 88 in T-cadherin.…”

Section: Resultsmentioning

confidence: 99%

“…3C and 4). Fourth, studies with N-cadherin highlighted the relevance of an intermolecular salt-bridge between the N-terminal positively charged amide group and the negatively charged carboxylate of Glu-89 for dimer formation (41). Based on the observed distances in the calculated Tcad1 structures, ionic interactions between the N-terminal amide and Asp-26 as well as Asp-28 occur more often than with Glu-88 (Fig.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain

Dames

Bang

Häußinger

et al. 2008

Journal of Biological Chemistry

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T-cadherin is unique among the family of type I cadherins, because it lacks transmembrane and cytosolic domains, and attaches to the membrane via a glycophosphoinositol anchor. The N-terminal cadherin repeat of T-cadherin (Tcad1) is ≈30% identical to E-, N-, and other classical cadherins. However, it lacks many amino acids crucial for their adhesive function of classical cadherins. Among others, Trp-2, which is the key residue forming the canonical strand-exchange dimer, is replaced by an isoleucine. Here, we report the NMR structure of the first cadherin repeat of T-cadherin (Tcad1). Tcad1, as other cadherin domains, adopts a ␤-barrel structure with a Greek key folding topology. However, Tcad1 is monomeric in the absence and presence of calcium. Accordingly, lle-2 binds into a hydrophobic pocket on the same protomer and participates in an N-terminal ␤-sheet. Specific amino acid replacements compared to classical cadherins reduce the size of the binding pocket for residue 2 and alter the backbone conformation and flexibility around residues 5 and 15 as well as many electrostatic interactions. These modifications apparently stabilize the monomeric form and make it less susceptible to a conformational switch upon calcium binding. The absence of a tendency for homoassociation observed by NMR is consistent with electron microscopy and solid-phase binding data of the full T-cadherin ectodomain (Tcad1-5). The apparent low adhesiveness of T-cadherin suggests that it is likely to be involved in reversible and dynamic cellular adhesion-deadhesion processes, which are consistent with its role in cell growth and migration.T-cadherin, also known as truncated, H-, or heart cadherin is an unusual member of the family of type I cadherins that function in calcium-dependent homophilic cell-cell adhesion and thereby govern processes important for tissue morphogenesis such as cell recognition, sorting, coordinated cell movements, and polarity (1). T-cadherin is widely expressed in the brain and the cardiovascular system, but absent or strongly depleted in many cell cancer lines (2-5). The expression of T-cadherin is regulated in response to growth factor signals, aryl hydrocarbon receptor ligands, and oxidative stress (6 -8). T-cadherin shares the extracellular five cadherin repeats with other type I cadherins but lacks the transmembrane and cytosolic domains and instead attaches to the membrane via a glycophosphoinositol (GPI) 5 anchor (Fig. 1A) (9). Classical cadherins accumulate at adherens junctions, where they interact via their cytoplasmic domain with integrins, catenins, and specific kinases. In contrast, T-cadherin has been localized within lipid rafts of the plasma membrane, is targeted to the apical surface in polarized epithelial cells, and redistributed to the leading edge of migrating cells (10 -12). Based on these observations, it has been suggested that T-cadherin functions as a signaling molecule involved e.g. in angiogenesis, cell growth, proliferation, migration, and survival (8,13,14). T-cadherin is a receptor f...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain

Dames

Bang

Häußinger

et al. 2008

Journal of Biological Chemistry

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show abstract

“…The salt bridge is also conserved in type II cadherins (Patel et al 2006). This salt bridge has been shown to play a key role in forming the stand swapped interface (Harrison et al 2005). However, many of the reported affinity measurements used bacterially produced proteins that contain extensions at their amino-termini.…”

Section: Unique Properties Of Strand-swap Bindingmentioning

confidence: 99%

Structure and Biochemistry of Cadherins and Catenins

Shapiro¹,

Weis²

2009

Cold Spring Harbor Perspectives in Biology

404

355

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Classical cadherins mediate specific adhesion at intercellular adherens junctions. Interactions between cadherin ectodomains from apposed cells mediate cell -cell contact, whereas the intracellular region functionally links cadherins to the underlying cytoskeleton. Structural, biophysical, and biochemical studies have provided important insights into the mechanism and specificity of cell-cell adhesion by classical cadherins and their interplay with the cytoskeleton. Adhesive binding arises through exchange of b strands between the first extracellular cadherin domains (EC1) of partner cadherins from adjacent cells. This "strand-swap" binding mode is common to classical and desmosomal cadherins, but sequence alignments suggest that other cadherins will bind differently. The intracellular region of classical cadherins binds to p120 and b-catenin, and b-catenin binds to the F-actin binding protein a-catenin. Rather than stably bridging b-catenin to actin, it appears that a-catenin actively regulates the actin cytoskeleton at cadherin-based cell -cell contacts.

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“…It is more likely, however, that both dimers-the cadherin dimer detected in the NMR study and the unstable dimer detected in our work-correspond to the strand dimer. The instability of the strand dimer has been explained by competition between intramolecular and intermolecular docking of Trp156 in conjunction with the relatively low energy barrier for Trp156 exchange (Chen et al, 2005, Harrison et al, 2005. The high-energy barrier, which provides stability for the strand dimer, must be based on much more extensive swapping.…”

Section: Stable and Unstable Cadherin Dimers Are Similar In Structurementioning

confidence: 99%

Stable and Unstable Cadherin Dimers: Mechanisms of Formation and Roles in Cell Adhesion

Troyanovsky

Laur

Troyanovsky

2007

MBoC

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Numerous attempts to elucidate the strength of cadherin dimerization that mediates intercellular adhesion have produced controversial and inconclusive results. To clarify this issue, we compared E-cadherin dimerization on the surface of living cells with how the same process unfolds on agarose beads. In both cases, dimerization was monitored by the same site-specific cross-linking assay, greatly simplifying data interpretation. We showed that on the agarose surface under physiological conditions, E-cadherin produced a weak dimer that immediately dissociated after the depletion of calcium ions. However, either at pH 5 or in the presence of cadmium ions, E-cadherin produced a strong dimer that was unable to dissociate upon calcium depletion. Both types of dimers were W156-dependent. Remarkably, only the strong dimer was found on the surface of living cells. We also showed that the intracellular cadherin region, the clustering of which through catenins had been proposed as stabilizer of weak intercadherin interactions, was not needed, in fact, for cadherin junction assembly. Taken together, our data present convincing evidence that cadherin adhesion is based on high-affinity cadherin-cadherin interactions.

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Cadherin adhesion depends on a salt bridge at the N-terminus

Cited by 40 publications

References 42 publications

Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain

Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain

Structure and Biochemistry of Cadherins and Catenins

Stable and Unstable Cadherin Dimers: Mechanisms of Formation and Roles in Cell Adhesion

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