Conserved motifs: DRE, DXNDNAPXF, and DXD
Description
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 [MEDLINE:2197976], [MEDLINE:],[MEDLINE: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 [MEDLINE: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 .
Description text from InterPro entry IPR002126
From Cadherin Superfamily Genes webpage at: http://www.mrc-lmb.cam.ac.uk/genomes/Cadherins/cad_web_pages.html
Cadherins are Calcium dependant cell adhesion molecules. They play an important role in embryonic morphogenesis and the formation of solid tissues.
Classical cadherins consist of 5 tandemly repeated extracellular cadherin domains, a transmembrane region and a cytoplasmic region, (eg. CAD1_CHICK). Protocadherins also exist, they have many more tandemly repeated cadherin domains, (eg. FAT_DROME).
Cadherins are normally anchored via their cytoplasmic region through catenins to cytoskeletal actin microfilaments.
Two cadherins within one cell dimerise through homophilic contacts on domain 1. A dimer can then adhere, (forming anti-parallel contacts creating a zipper formation) to two other dimers on neighbouring cells.
Reference:
The cadherin superfamily of proteins in Caenorhabditis elegans and Drosophila melanogaster.
Emma Hill, Ian Broadbent, Cyrus Chothia & Jonathan Pettitt. JMB. (2001), 305, (5), 1011-1024.
From The Cadherin Resource at: http://calcium.uhnres.utoronto.ca/cadherin/pub_pages/general/index.htm
Classical cadherins have a well conserved cytoplasmic domains. Chordate classic cadherins have an extracellular domain organization composed of five cadherin repeats. Chordate classical cadherins can be further sub-divided into type I and type II. Type I cadherins have a His-Arg-Val sequence in the N-terminal cadherin repeat. Type II cadherins are all chordate classical cadherins not in type I.
Nonchordate classic cadherins have an extracellular domain organization composed of at least two cadherin repeats. In contrast to chordates, nonchordate classic cadherins have a variable number of repeats in the extracellular domain (e.g. HMR-1 in C. elegans has 2 repeats, and DN-cadherin in Drosophila has 15 repeats). Also, they have additional domains that are inserted between the cadherin repeats and the transmembrane domain. These domains include one or two Laminin A G domains, several cysteine-rich repeats with similarity to the epidermal growth factor (EGF).
Desmosomal cadherins are expressed in desmosomes and are essential for desmosome formation. They contain 5 extracellular cadherin repeats like chordate classical cadherins. Tyrosine receptor kinase (RET) cadherins have a tyrosine kinase domain in its cytoplasmic domain. The extracellular domain contains one cadherin repeat.
Fat-like cadherins have a very large extracellular domains with many cadherin repeats (19 in CDH-3, 27 in Dachsous, 34 in Fat, hFat, and rFAT). As well, Fat, hFat, rFAT and CDH-3 contain epidermal growth factor (EGF)-like and Laminin AG-domain-like regions. These regions are localized between the cadherin and transmembrane domains. Fat-like cadherins may function in adhesion or signaling, or both.
Flamingo cadherins contain a seven-pass transmembrane receptor which shows some similarity to the secretin family of G-protein linked receptors. The large extracellular domain of Flamingo contains nine cadherin repeats, two globular laminin motifs, and four cystein-rich EGF motifs. Also present is a subdomain located between the last cadherin repeat and the first EGF domain which is highly conserved across species. This region is known as the Flamingo box.