| Abstract | This entry represents domains with an immunoglobulin-like beta-sandwich fold, consisting of 7 strands in two sheets with a Greek key topology. Such domains are found in cadherin, as well as at the N-terminal of dystroglycan. Dystroglycan is a cell surface receptor consisting of two subunits: alpha-dystroglycan, extracellular and highly glycosylated, and beta-dystroglycan, spanning the cell membrane. It is a pivotal member of the dystrophin-glycoprotein complex and is involved in a wide variety of important cellular processes such as the stabilisation of the muscle fiber sarcolemma or the clustering of acetylcholine receptors [ 11909544, 15326183, 16410545].
Cadherins are a family of adhesion molecules that mediate Ca2+-dependent cell-cell adhesion in all solid tissues of the organism which modulate a wide variety of processes including cell polarisation and migration [2197976,14570569]. Cadherin-mediated cell-cell junctions are formed as a result of interaction between extracellular domains of identical cadherins, which are located on the membranes of the neighbouring cells. The stability of these adhesive junctions is ensured by binding of the intracellular cadherin domain with the actin cytoskeleton. There are a number of different isoforms distributed in a tissue-specific manner in a wide variety of organisms. Cells containing different cadherins tend to segregate in vitro, while those that contain the same cadherins tend to preferentially aggregate together. This observation is linked to the finding that cadherin expression causes morphological changes involving the positional segregation of cells into layers, suggesting they may play an important role in the sorting of different cell types during morphogenesis, histogenesis and regeneration. They may also be involved in the regulation of tight and gap junctions, and in the control of intercellular spacing. Cadherins are evolutionary related to the desmogleins which are component of intercellular desmosome junctions involved in the interaction of plaque proteins.
Structurally, cadherins comprise a number of domains: classically, these include a signal sequence; a propeptide of around 130 residues; a single transmembrane domain and five tandemly repeated extracellular cadherin domains, 4 of which are cadherin repeats, and the fifth contains 4 conserved cysteines and a N-terminal cytoplasmic domain [11736639]. However, proteins are designated as members of the broadly defined cadherin family if they have one or more cadherin repeats. A cadherin repeat is an independently folding sequence of approximately 110 amino acids that contains motifs with the conserved sequences DRE, DXNDNAPXF, and DXD. Crystal structures have revealed that multiple cadherin domains form Ca2+-dependent rod-like structures with a conserved Ca2+-binding pocket at the domain-domain interface. Cadherins depend on calcium for their function: calcium ions bind to specific residues in each cadherin repeat to ensure its proper folding, to confer rigidity upon the extracellular domain and is essential for cadherin adhesive function and for protection against protease digestion. |
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