Cadherin domains

The results of domain swap experiments, in which an extracellular domain of one kind of cadherin is replaced with the corresponding domain of a different cadherin, have indicated that the specificity of binding resides, at least in part, in the most distal extracellular domtiin, the N-terminal domain. In the past, cadherin-mediated adhesion was commonly thought to require only head-to-head Interactions between the N-terminal domains of cadherin oligomers on adjacent cells, as depicted in Figure 6-3. However, the results of some experiments suggest that under some experimental conditions at least three cadherin domains from each molecule, not just the N-terminal domains, participate by inter-digitation in trans associations. 

Cadherins (Calcium-dependent adhesion proteins) are transmembrane proteins, which consist of an extracellular domain composed of cadherin-repeats, a transmembrane domain, and a cytoplasmic domain that interacts with catenins and/or other cytoplasmic proteins. 

Cadherins are a superfamily of Ca2+-sensitive cell-cell adhesion molecules, which cause homophilic cell interactions. Cadherins can be divided into different subfamilies, namely, classical cadherins, desmosomal cadherins, protocadherins, and nonconventional cadherins (7TM cadherins, T-cadherin, FAT). Classical cadherins are often denoted by a prefix reflecting their principal expression domains e.g., E is epithelial, N is neuronal, and P is placental. However, this classification is not stringent, as for instance E-cadherin can also be found in certain neuronal tissues, and N-cadherin is also found in epithelial cells. Among the desmosomal cadherins, two subfamilies can be distinguished the desmocollins 1-3 and the desmogleins 1-4. 

The extracellular domain of cadherins consists of a variable number of a repeated sequence of about 110 amino acids. This sequence is termed the cadherin repeat and resembles in overall structure, but not in sequence, the Ig like domains. The cadherin repeat is the characteristic motive common to all members of the cadherin superfamily. Classical and desmosomal cadherins contain five cadherin repeats, but as many as 34 repeats have been found in the FAT cadherin (see below). Cadherins are calcium-dependent cell adhesion molecules, which means that removal of Ca2+, e.g., by chelating agents such as EDTA, leads to loss of cadherin function. The Ca2+-binding pockets are made up of amino acids from two consecutive cadherin repeats, which form a characteristic tertiary structure to coordinate a single Ca2+ion [1]. 

The classical cadherins are translated as precursor because they are N-terminally cleaved to reveal the mature proteins. This processing is required to activate the cell adhesion function of cadherins. Cadherins interact in trans (i.e., from opposite cells) via the most N-terminal cadherin rqDeats. A short amino acid sequence within this repeat, histidine-alanine-valine (HAV), has been implicated in mediating cell-cell contacts as HAV peptides can disrupt cadherin-dependent cell adhesion. Besides the trans-interactions of cadherins, the extracellular domains are also capable of forming cis-dimers through lateral amino acid contacts between cadherin molecules on one cell. This dimerization again mainly involves the first cadherin repeat. A zipper model based on the pattern of alternating cis- and trans-dimers [1] for the adhesive interactions has been proposed. 

Several nonconventional cadherins that contain cadherin repeats have been described but they have specific features not found in the classical cadherins [1]. The cadherin Flamingo, originally detected in Drosophila, contains seven transmembrane segments and in this respect resembles G protein-coupled receptors. The extracellular domain of Flamingo and its mammalian homologs is composed of cadherin repeats as well as EGF-like and laminin motifs. The seven transmembrane span cadherins have a role in homotypic cell interactions and in the establishment of cell polarity. The FAT-related cadherins are characterized by a large number of cadherin repeats (34 in FAT and 27 in dachsous). Their cytoplasmic domains can bind to catenins. T- (=truncated-)cadherin differs from other cadherins in that it has no transmembrane domain but is attached to the cell membrane via a glycosylpho-sphatidylinositol anchor. 

The cytoplasmic domains of protocadherins are unrelated to those of classical cadherins. They do not bind catenins and it is not clear whether they are associated with the cytoskeleton [1]. Some protocadherins interact with the c- src-related kinase Fyn, indicating a role in signal transduction (see below). 

Poly(3HB) depolymerase with cadherin-like linker domain 57... 

Yet another family of junction adhesion molecules (JAMs) was recently located at the tight junctions of both endothelial and epithelial cells. The intracellular domain of JAM-1 also interacts with structural and signaling proteins, such as ZO-1 and cingulin. Lastly, the molecular organization of the endothelial cell junctions includes two other cell-cell contact Ca2+-dependent cadherin-catenin systems. These make up the adherens junction common to all endothelial cell junctions. 

FIGURE 7-4 Basic cadherin structure. Two types of cadherin are present in the nervous system the classic cadherins with five extracellular domains and the protocadherins with six extracellular domains. For the classic cadherins, the binding partners on the cytoplasmic side include the a, P and y catenins. The binding partners for the protocadherins have not yet been identified. 

A recent crystal structure based model [20] for the structure of C-cadherin postulates that the five extracellular domains EC1-EC5 protrude from the cell surface as a curved rod. The structural analysis of C-cadherin reveals that the molecules facing each other across apposed cell surfaces are antiparallel to one another, forming a dimeric interaction termed a strand dimer (Fig. 7-5). This forms the functional unit that is likely to mediate adhesion between cell surfaces. The structure from this recent paper allows the prediction of both cis and trans interfaces that together result in a lattice and not, as previously believed, an adhesion zipper. This new model allows for a mechanism by which adhesion plates or puncta might be generated, such as are formed at CNS synapses [21, 22], adherens junctions and desmosomes [23], all cadherin based organelles. 

Kintner, C. Regulation of embryonic cell adhesion by the cadherin cytoplasmic domain. Cell 69 225-236,1997. 

Scheme 13.7 Solid-phase synthesis of a glycopeptide from the homophilic recognition domain of epithelial Cadherin 1 using the new coupling reagent PfPyU.

At least three other families of plasma membrane proteins are also involved in surface adhesion (Fig. 11-22). Cadherins undergo homophilic ( with same kind ) interactions with identical cadherins in an adjacent cell. Immunoglobulin-like proteins can undergo either homophilic interactions with their identical counterparts on another cell or heterophilic interactions with an integrin on a neighboring cell. Selectins have extracellular domains that, in the presence of Ca2+, bind specific polysaccharides on the surface of an adjacent cell. Selectins are present primarily in the various types of blood cells and in the endothelial cells that line blood vessels (see Fig. 7-33). They are an essential part of the blood-clotting process. 

The cadherins are calcium-dependent adhesion proteins that mediate direct cell-cell interactions.295 296 The external parts of the cadherins also have repeated structural domains with the Ig fold.297 298b They have high affinity for each other, allowing cadherins from two different cells to interact and tie the cells together with a zipper-like interaction that is stabilized by the bound Ca2+ ions,297 300 and may be relatively long-lived. The gene for cadherin E is often mutated in breast cancers and may be an important tumor suppressor gene (Box 11-D).301... 

Cacodylic acid, pKa value of 99 Cadherin(s) 187,407 domains 408s Cadmium 317... 

Meigs, T. E., Fields, T. A., McKee, D. D., and Casey, P.J. (2001). Interaction of G alpha 12 and G alpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta-catenin release. Proc. Natl. Acad. Sci. USA 98, 519-524. 

Fig. 3. A comparison of cell-cell and cell-substrated anchoring junctions. (A) Desmosomes anchor keratin filaments through desmoplakin. One half of a desmosome, which is an intercellular junction that anchors intermediate filaments (IFs) to the plasma membrane, is shown. The transmembrane desmosomal cadherins, desmogleins (Dsg) and desmocollins (Dsc), mediate adhesion through their extracellular domains, and associate with plakophilins (Pkp) and plakoglobin (Pg) through their cytoplasmic domains. These proteins in turn interact with the N-terminus of the plakin family member desmoplakin, which anchors IF to the junction through its G-terminus. (B) Endothelial VE-cadherin-based junctions anchor vimentin through...

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