Cadherins, calcium binding

CaBP (Calcyclin), 46 454-456 Cadherins, calcium binding in, 46 483-484 Cadmium... 

Anders, J., Kjar, S., and Ibanez, G. F. (2001). Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site./. Biol. Chem. 276, 35808-35817. 

Cadherins are calcium-dependent cell adhesion proteins that mainly participate in interactions with cadherins, located on other cells. Cadherins have five similar extracellular domains some of which have calcium-binding sites, and an intracellular C-terminal domain that interacts with the actin cytoskeleton. Different cadherins are named according to the tissues were they were first found. E-cadherins were found in many epithelial cells. N-cadherins are present in nerves and muscle and P-cadherin are present in placental cells. 

There are several types of extracellular calcium-binding proteins. The majority of these proteins such as cadherins, integrins and growth factors, are from eukaryotic systems. 

Figure 17 The ditneric structure ofE-cadherinECl-2 (lEDH) (a). Two polypeptide chains and their bound calcium are shown in different colors, (b) A close-up view of the calcium-binding sites. The calcium ligand residues on chain A are labeled. Several ligands are shared by different calcium ions. All calcium binding in cadherin belongs to the discontinuous site class...

The adhesion of cells to each other is normally due to interactions that involve a number of proteins of the extracellular matrix and the plasma membrane. Cadherin is a membrane-boimd protein. The N terminus of cadherin is extracellular. The N termini of cadherins sticking out of adjacent cells bind to each other. This interaction requires calcivun ions, hence the name Cadherin. An intracellular interaction is also required for adhesion to occur between cells. The C terminus of cadherin contacts the cytosol and binds to a protein called catenin (pronounced ca-TEE-nin). Catenin, in turn, binds to the cytoskeleton. The cytoskeleton is a network of proteins that crisscross about the plasma membrane and through the cell. Defects in the cadherin gene have been found in many samples of colorectal cancer. These mutations tend to occur in the N-terminal region, i.e., in the extracellular calcium-binding domain. 

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]. 

Figure 18 The structure of the extracellular region of Ep-cadherm (1L3W). Calcium ions bind to the loops between each two adjacent domains and the whole protein in the structure forms a curvature. N-acetyl-D-glucosamine molecules attached to the cadherin surface are in gray...

Neural recognition molecules, also called cellcell adhesion molecules (CAMs), are involved in neuron-neuron and neuron-glia interactions, e.g. neuronal migration and neurite outgrowth (Doherty and Walsh, 1989). In general, CAMs can be divided into (1) molecules of the immunoglobulin superfamily (Ig-family), which operate in a calcium-independent fashion (2) cadherins (CADs), which bind in a calcium-dependent manner and (3) other molecules (see below reviewed in Edelman and Crossin, 1991). 

The cadherin family of glycoproteins mediates calcium- dependent cell-cell adhesion. Cadherins frorm intercellular complexes binding cells together (Fig. 18.12A). They are anchored intracellularly by catenins, which bind to actin filaments. Loss of E-cadherin expression may contribute to the ability of cancer cells to detach and migrate in metastasis. Individuals who inherit a mutation in E cadherin (this mutation is designated as CDHl) are sharply predisposed to developing diffuse type gastric cancer. 

Cadherins are the main receptors for calcium-dependent cell-cell adhesion in most solid tissues (Alberts et al. 2002). Besides being responsible for the mechanical stability, they coordinate the integration of cells in functional structures like the epithelium and control cell movement in tissue development and organization, especially during embryogenesis (Table 5.3). Classical cadherins are transmembrane glycoproteins, which bind almost exclusively to the same type of receptor expressed on the other cell in a homophilic manner (Fig. 5.2). The intracellular domain is connected to the cytoskeleton via a group of anchor proteins known as catenins (Pettitt 2005 Reynolds 2007). This link-... 

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