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Review
. 2009 Sep;1(3):a003053.
doi: 10.1101/cshperspect.a003053.

Structure and biochemistry of cadherins and catenins

Lawrence Shapiro  1 , William I Weis
Affiliations
Review

Structure and biochemistry of cadherins and catenins

Lawrence Shapiro et al. Cold Spring Harb Perspect Biol. 2009 Sep.

Abstract

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 beta 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 beta-catenin, and beta-catenin binds to the F-actin binding protein alpha-catenin. Rather than stably bridging beta-catenin to actin, it appears that alpha-catenin actively regulates the actin cytoskeleton at cadherin-based cell-cell contacts.

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Figures

Figure 1.
Figure 1.
Domain structure of cadherins. The best understood cadherins are the “classical” cadherins of vertebrates, and the closely related desmosomal cadherins. These proteins contain a prodomain (P) immediately following the signal sequence, which is removed by proteolysis. Mature classical and desmosomal cadherins have ectodomains composed of five extracellular cadherin (EC) repeats, a single transmembrane region, and a cytoplasmic domain that interacts with either β-catenin (classical cadherins) or plakoglobin, also known as γ-catenin (desmosomal cadherins). Other cadherin family members have widely differing domain structures, as illustrated by the diagram of Drosophila DN-cadherin.
Figure 2.
Figure 2.
Structures of cadherins. (A and B) Crystal structure of the ectodomain from C-cadherin. (A) Adhesive dimer, joined through the strand-swap interface formed between EC1 domains. (B) Close-up rotated view of the strand-swap interface, highlighting the conserved “anchor” residue Trp 2. Bound calcium ions are shown as green spheres. (C–F) Possible cadherin junction structures. Cryoelectron tomography has been used to acquire three-dimensional images of desmosome junctions in two cases. One of these (C) by He and colleagues (He et al. 2003) examined plastic-embedded samples and revealed a poorly ordered structure. Another (D) by Al-Amoudi and colleagues (Al-Amoudi et al. 2007) examined frozen hydrated samples and used averaging procedures, and revealed a uniformly repeating structure. Crystals of C-cadherin (D and E) are arranged in lattice layers suggestive of a junction structure. These structures are made up of intersecting lines of cadherins (D), which together form a two-dimensional array (E).
Figure 3.
Figure 3.
Strand-swap binding by classical cadherins. (A) 3D domain swapping by cadherin EC1 domains. 3D domain swapping provides a simple mechanism for constructing homophilic interfaces. A protein made up of a “main” domain and a “swapping” domain connected by a flexible region can form a “closed” monomer, or a multimer (a dimer in the case of cadherins). These two molecular configurations compete with one another, leading to weak binding affinities. (B) Comparison of strand-swap interfaces of type I and type II classical cadherins. Although folding topology is identical, these two subfamilies have incompatible binding interfaces. Type II cadherins include two conserved Trp anchor residues, rather than one, and form a hydrophobic interface that runs the length of the EC1 domain.
Figure 4.
Figure 4.
β-Catenin structure and its complex with E-cadherin cytoplasmic domain. (A) Three-dimensional structure of the β-catenin arm repeat region in complex with the E-cadherin cytoplasmic domain (Huber and Weis 2001). The arm repeats are formed by three helices, colored gray (H1 and H2) and blue (H3). Residues 134–161, which include the α-catenin binding site and a portion of the first arm repeat, form a single helix in this particular crystal structure (cyan). E-cadherin is divided into five regions of primary structure that are indicated in distinct colors. (B) The β-catenin primary structure. Binding sites for cadherin and α-catenin are indicated.
Figure 5.
Figure 5.
α-Catenin structure and β-catenin binding. (A) The primary structure of α-catenin, showing interaction sites mapped by direct binding and/or crystallography. The dimerization domain is shown in yellow; the preceding helix required for β-catenin binding is shown in blue. The M-domain is shown in light green, and the actin-binding domain in dark green. (B) The three-dimensional structure of the α-catenin dimerization region 82–264 (Pokutta and Weis 2000). The protomers of the α-catenin dimer are shown in yellow and orange. Residues 57–81, which were not in the crystallized construct and are flexibly linked to the dimerization domain, are schematically illustrated by the dashed blue box. (C) The βα-catenin chimera primary structure is shown to the right of the crystal structure. The helices of the dimerization region 82–264 are colored in yellow, and the helix formed by 57–81 in blue. The α-catenin binding region of β-catenin is shown in red.
Figure 6.
Figure 6.
Model of α-catenin function in actin polymerization and reorganization in developing cell–cell contacts. See text for details. From Pokutta et al. 2008.
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