Cadherin-mediated cell–cell adhesion: sticking together as a family (original) (raw)
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T-cadherin structures reveal a novel adhesive binding mechanism
Nature Structural & Molecular Biology, 2010
a r t i c l e s Cadherins are a large family of cell-surface transmembrane proteins that mediate intercellular adhesion in vertebrates and invertebrates 1-3 . Sequence analysis has revealed numerous cadherin subfamilies 4,5 , including the classical cadherins, whose biological roles in cell recognition, development and tissue homeostasis have been well characterized: 19 classical cadherins (6 members of the type I and 13 members of the type II subfamilies) are conserved in vertebrate genomes 4,5 . Type I cadherins are typically expressed broadly in epithelia, whereas type II cadherins have more finely grained expression patterns often restricted to the nervous system and vasculature 6-8 . Numerous nonclassical cadherins have been characterized, including the gene-clustered protocadherins 9 , flamingo-like cadherins with receptor-like sevenhelix transmembrane regions 10 and very large cadherins such as cadherin-23, which forms 'rope-like' helical structures between adjacent stereocilia of acousticolateral hair cells 4,5,11 .
Functional Analysis of the Structural Basis of Homophilic Cadherin Adhesion
Biophysical Journal, 2003
The structures of many cell surface adhesion proteins comprise multiple tandem repeats of structurally similar domains. In many cases, the functional significance of this architecture is unknown, and there are several cases in which evidence for individual domain involvement in adhesion has been contradictory. In particular, the extracellular region of the adhesion glycoprotein cadherin consists of five tandemly arranged domains. One proposed mechanism postulated that adhesion involves only trans interactions between the outermost domains. However, subsequent investigations have generated several competing models. Here we describe direct measurements of the distance-dependent interaction potentials between cadherin mutants lacking different domains. By quantifying both the absolute distances at which opposed cadherin fragments bind and the quantized changes in the interaction potentials that result from deletions of individual domains, we demonstrate that two domains participate in homophilic cadherin binding. This finding contrasts with the current view that cadherins bind via a single, unique site on the protein surface. The potentials that result from interactions involving multiple domains generate a novel, modular binding mechanism in which opposed cadherin ectodomains can adhere in any of three antiparallel alignments.
Linking molecular affinity and cellular specificity in cadherin-mediated adhesion
Proceedings of The National Academy of Sciences, 2009
Many cell-cell adhesive events are mediated by the dimerization of cadherin proteins presented on apposing cell surfaces. Cadherinmediated processes play a central role in the sorting of cells into separate tissues in vivo, but in vitro assays aimed at mimicking this behavior have yielded inconclusive results. In some cases, cells that express different cadherins exhibit homotypic cell sorting, forming separate cell aggregates, whereas in other cases, intermixed aggregates are formed. A third pattern is observed for mixtures of cells expressing either N-or E-cadherin, which form distinct homotypic aggregates that adhere to one another through a heterotypic interface. The molecular basis of cadherin-mediated cell patterning phenomena is poorly understood, in part because the relationship between cellular adhesive specificity and intermolecular binding free energies has not been established. To clarify this issue, we have measured the dimerization affinities of N-cadherin and E-cadherin. These proteins are similar in sequence and structure, yet are able to mediate homotypic cell patterning behavior in a variety of tissues. N-cadherin is found to form homodimers with higher affinity than does E-cadherin and, unexpectedly, the N/Ecadherin heterophilic binding affinity is intermediate in strength between the 2 homophilic affinities. We can account for observed cell aggregation behaviors by using a theoretical framework that establishes a connection between molecular affinities and cell-cell adhesive specificity. Our results illustrate how graded differences between different homophilic and heterophilic cadherin dimerizaton affinities can result in homotypic cell patterning and, more generally, show how proteins that are closely related can, nevertheless, be responsible for highly specific cellular adhesive behavior.
Journal of Cell Biology, 1998
Cadherin cell–cell adhesion molecules form membrane-spanning molecular complexes that couple homophilic binding by the cadherin ectodomain to the actin cytoskeleton. A fundamental issue in cadherin biology is how this complex converts the weak intrinsic binding activity of the ectodomain into strong adhesion. Recently we demonstrated that cellular cadherins cluster in a ligand-dependent fashion when cells attached to substrata coated with the adhesive ectodomain of Xenopus C-cadherin (CEC1-5). Moreover, forced clustering of the ectodomain alone significantly strengthened adhesiveness (Yap, A.S., W.M. Brieher, M. Pruschy, and B.M. Gumbiner. Curr. Biol. 7:308–315). In this study we sought to identify the determinants of the cadherin cytoplasmic tail responsible for clustering activity. A deletion mutant of C-cadherin (CT669) that retained the juxtamembrane 94–amino acid region of the cytoplasmic tail, but not the β-catenin–binding domain, clustered upon attachment to substrata coated ...
Inside-out regulation of E-cadherin conformation and adhesion
ABSTRACTCadherin cell-cell adhesion proteins play key roles in tissue morphogenesis and wound healing. Cadherin ectodomains bind in two conformations, X-dimers and strand-swap dimers, with different adhesive properties. However, the mechanisms by which cells regulate ectodomain conformation are unknown. Cadherin intracellular regions associate with several actin-binding proteins including vinculin, which are believed to tune cell-cell adhesion, solely by remodeling the actin cytoskeleton. Here, we demonstrate that vinculin association with the cadherin cytoplasmic region, also allosterically regulates ectodomain structure and adhesion, by converting weaker X-dimers into stronger strand-swap dimers. We also show that in epithelial cells, only half of apical cadherins are linked to the cytoskeleton. Furthermore, only 70% of apical cadherins form strand-swap dimers while the remaining form X-dimers, which provides cells with two cadherin pools with different adhesive properties. Our re...
Cell Reports, 2018
Type II cadherins are cell-cell adhesion proteins critical for tissue patterning and neuronal targeting but whose molecular binding code remains poorly understood. Here, we delineate binding preferences for type II cadherin cell-adhesive regions, revealing extensive heterophilic interactions between specific pairs, in addition to homophilic interactions. Three distinct specificity groups emerge from our analysis with members that share highly similar heterophilic binding patterns and favor binding to one another. Structures of adhesive fragments from each