The coloured areas represent regions of similarity between the two proteins. The degrees of amino-acid identity are indicated as percentages. The magenta region in vinculin represents the proline-rich hinge segment. Actin-binding domains are marked as the red open boxes (amino acids 697–906 for αE-catenin and 893–985/1016–1066 for vinculin). The intercellular adhesion modulation (M) domain (residues 509–643) of αE-catenin is marked as the blue open box. The numbers correspond to amino acids of the protein sequence. VH, vinculin-homology domain.

a | Initial cell–cell contacts are formed by opposing E-cadherin–β-catenin complexes at the tips of filopodia or lamellipodia. These initial contacts are nascent adherens junctions and are termed puncta. b | In the presence of αE-catenin, formin and other proteins such as VASP (vasodilator-stimulated phosphoprotein) that bind to αE-catenin and/or the actin cytoskeleton, bundles of radial actin cables assemble on each side of the puncta and form anchors to the underlying cortical actin ring. c | As a consequence of actin reorganization, mature adherens junctions are formed.

The electron micrograph and corresponding schematic depict the main types of intercellular junction in epithelial cells. Tight junctions are composed of transmembrane proteins that link to the actin cytoskeleton and prevent the leakage of small molecules through intercellular spaces. Adherens junctions are formed by homophilic interactions between E-cadherin molecules, and are connected to the actin network through β- and α-catenins. They function to coordinate the actin cytoskeleton across an epithelial sheet. Desmosomes are composed of desmosomal cadherins that are linked to intermediate filaments and integrate the intermediate-filament network across the epithelial sheet. Electron micrograph courtesy of H. Amalia Pasolli, Rockefeller University, New York, USA.

Mutations in the αN-catenin gene underlie the genetic defect in the ataxic cerebellar deficient folia (cdf)-mutant mice. The cerebella of cdf/cdf-mutant mice show hypoplasia and abnormal lobulation. a | A schematic representation of the midline sagittal sections from wild-type and cdf/cdf-mutant mouse brain cerebella shows scattered Purkinje cells in the more central white matter and abnormal lobulation (blue stars). The magnified region (b) shows the structure of the cerebellar cortex (the grey matter), which includes the cell bodies and dendrites of the Purkinje cells; the axons of the granule cells; and the cell bodies, dendrites and axons of the basket cells.

This schematic of αE-catenin illustrates its three vinculin homology (VH) domains (VH1–VH3). The direct binding partners for αE-catenin are listed on the right, and the corresponding domain diagrams denote the regions and encompassing amino-acid residues of αE-catenin that have been identified as biochemically essential for the interaction. αE-catenin interacts with E-cadherin–β-catenin complexes through its amino-terminal β-catenin-binding domain. In solution, αE-catenin forms a homodimer through its dimerization domain. When αE-catenin associates with E-cadherin–β-catenin complexes, however, the αE-catenin homodimer dissociates, and heterodimers of α- and β-catenin are formed. The intercellular adhesion modulation (M) domain, which partially includes the VH2 domain of αE-catenin, defines the segments of αE-catenin that are necessary for mediating intercellular adhesion. The carboxy-terminal region, which includes the VH3 domain of αE-catenin, overlaps with the filamentous (F)-actin-binding domain. The vinculin-, α-actinin- and formin-1-binding domains on αE-catenin facilitate organization of the F-actin cytoskeleton and the regulation of actin dynamics during the formation of stable intercellular adhesions.

The crucial functions of αE-catenin and vinculin are to mediate protein–protein and protein–phospholipid interactions. Proteins composed of tandemly repeated α-helical bundles provide a structural framework for the assembly of multiprotein complexes. a | View of the αE-catenin M-fragment structure with two four-helix domains (domains 1 and 2) coloured from the amino terminus (blue) to the carboxyl terminus (red). Letter labels for each of the helices are shown. b | The crystal structure of the carboxy-terminal part of vinculin comprises five helices (H0–H4). c | A comparison of the αE-catenin M-fragment domain 1 (red/orange; left) and domain 2 (green; middle) with the vinculin-tail domain (dark/light blue; right). Parts a and c courtesy of D. Barford and reproduced with permission from ref. 67 © (2001) Macmillan Magazines Ltd; part b courtesy of D. R. Critchley, Biochemistry Department, University of Leicester, UK and reproduced with permission from ref. 113 © (1999) Elsevier.

The extracellular region of E-cadherin, which contains extracellular cadherin (EC) domains, undergoes a Ca²⁺-dependent conformational change that allows it to homodimerize at the membrane. Through extracellular interactions with E-cadherins on a neighbouring cell, opposing cadherin dimers can integrate the actin cytoskeletons. Stabilization of intercellular adhesion requires the cytoplasmic domain of E-cadherin, which binds to β-catenin. β-catenin, in turn, binds α-catenin, which is central in recruiting a number of cytoskeletal proteins, including the filamentous (F)-actin-nucleating formin proteins (Fmn), and the actin-binding proteins vinculin, Ajuba, myosin VIIa, vezatin, α-actinin and members of the vasodilator-stimulated phosphoprotein (VASP) family of F-actin-elongating proteins. At least some of these interactions are essential in polymerizing and organizing actin into cables that help to seal membranes and integrate the actin cytoskeleton across the epithelial sheet. By contrast, p120 catenin (p120), which is related to β-catenin, binds to E-cadherin through a juxtamembrane domain and seems to function in cadherin turnover, perhaps by regulating cadherin trafficking. An emerging intercellular adhesion system (not shown), consisting of nectin and afadin, also has roles in the organization of a range of intercellular junctions. Nectin is a Ca²⁺-independent, immunoglobulin-like, intercellular adhesion molecule, and afadin is a nectin- and actin-filament-binding protein that connects nectin to the actin cytoskeleton78,79.