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Cadherin

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Principal interactions of structural proteins at cadherin-based adherens junction. Actin filaments are linked to α-actinin and to membrane through vinculin. The head domain of vinculin associates to E-cadherin via α-, β-, and γ-catenins. The tail domain of vinculin binds to membrane lipids and to actin filaments.

Cadherins (named for "calcium-dependent adhesion") are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, forming adherens junctions to bind cells within tissues together. They are dependent on calcium (Ca2+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with a large number of adaptor and signaling proteins, collectively referred to as the cadherin adhesome.

The cadherin superfamily includes cadherins, protocadherins, desmogleins, and desmocollins, and more.[1][2] In structure, they share cadherin repeats, which are the extracellular Ca2+-binding domains. There are multiple classes of cadherin molecule, each designated with a prefix (in general, noting the type of tissue with which it is associated). It has been observed that cells containing a specific cadherin subtype tend to cluster together to the exclusion of other types, both in cell culture and during development.[3] For example, cells containing N-cadherin tend to cluster with other N-cadherin-expressing cells. However, it has been noted that the mixing speed in the cell culture experiments can have an effect on the extent of homotypic specificity.[4] In addition, several groups have observed heterotypic binding affinity (i.e., binding of different types of cadherin together) in various assays.[5][6] One current model proposes that cells distinguish cadherin subtypes based on kinetic specificity rather than thermodynamic specificity, as different types of cadherin homotypic bonds have different lifetimes.[7]

Structure and Function

Cadherins are synthesized as polypeptides and undergo many post-translational modifications to become the proteins which mediate cell-cell adhesion and recognition.[8] These polypeptides are approximately 720–750 amino acids long. Each cadherin has a small cytoplasmic component, a transmembrane component, and the remaining bulk of the protein is extra-cellular (outside the cell). To date, over 100 types of cadherins in humans have been identified and sequenced.[9]

Development

Cadherins behave as both receptors and ligands for other molecules. During development, their behavior assists in properly positioning cells: they are responsible for the separation of the different tissue layers, and for cellular migration.[10] In the very early stages of development, E-cadherin (epithelial cadherin) is most greatly expressed. During the next stage, the development of the neural plate, N-cadherin (neural cadherin) is expressed and there is a decrease in E-cadherin. Finally, during the development of the notochord and the condensation of somites, E- P- and N-cadherin expression increases. After development, cadherins play a role in maintaining cell and tissue structure, and in cellular movement.[9] Regulation of cadherin expression can occur through promoter methylation among other epigenetic mechanisms.[11]

Tumour metastasis

The E-cadherin - catenin complex plays a key role in cellular adhesion; loss of this function has been associated with greater tumour metastasis.[12]

Types

Cadherin domain
Identifiers
SymbolCadherin
PfamPF00028
InterProIPR002126
SMARTCA
PROSITEPDOC00205
SCOP21nci / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1ncjA:272-373 1q1pA:269-368 1ff5B:269-368

1edhB:269-368 1l3wA:268-367 1nciA:164-258 1nchB:164-258 1ncg :164-258 1o6sB:159-253

1suh :161-255
Ribbon representation of a repeating unit in the extracellular E-cadherin ectodomain of the mouse (Mus Musculus) [13]

There are said to be over 100 different types of cadherins found in vertebrates, which can be classified into four groups: classical, desmosomal, protocadherins, and unconventional.[14][15] This large amount of diversity is accomplished by having multiple cadherin encoding genes combined with alternative RNA splicing mechanisms. Invertebrates contain fewer than 20 types of cadherins.[15]

Classical

Different members of the cadherin family are found in different locations.

  • CDH1 - E-cadherin (epithelial): E-cadherins are found in epithelial tissue
  • CDH2 - N-cadherin (neural): N-cadherins are found in neurons
  • CDH12 - cadherin 12, type 2 (N-cadherin 2)
  • CDH3 - P-cadherin (placental): P-cadherins are found in the placenta.

Desmosomal

Protocadherins

PCDH15; PCDH17; PCDH18; PCDH19; PCDH20; PCDH7; PCDH8; PCDH9; PCDHA1; PCDHA10; PCDHA11; PCDHA12; PCDHA13; PCDHA2; PCDHA3; PCDHA4; PCDHA5; PCDHA6; PCDHA7; PCDHA8; PCDHA9; PCDHAC1; PCDHAC2; PCDHB1; PCDHB10; PCDHB11; PCDHB12; PCDHB13; PCDHB14; PCDHB15; PCDHB16; PCDHB17; PCDHB18; PCDHB2; PCDHB3; PCDHB4; PCDHB5; PCDHB6; PCDHB7; PCDHB8; PCDHB9; PCDHGA1; PCDHGA10; PCDHGA11; PCDHGA12; PCDHGA2; PCDHGA3; PCDHGA4; PCDHGA5; PCDHGA6; PCDHGA7; PCDHGA8; PCDHGA9; PCDHGB1; PCDHGB2; PCDHGB3; PCDHGB4; PCDHGB5; PCDHGB6; PCDHGB7; PCDHGC3; PCDHGC4; PCDHGC5

FAT; FAT2; FAT4;

Unconventional/ungrouped

  • CDH9 - cadherin 9, type 2 (T1-cadherin)
  • CDH10 - cadherin 10, type 2 (T2-cadherin)
  • CDH4 - R-cadherin (retinal)
  • CDH5 - VE-cadherin (vascular endothelial)
  • CDH6 - K-cadherin (kidney)
  • CDH7 - cadherin 7, type 2
  • CDH8 - cadherin 8, type 2
  • CDH11 - OB-cadherin (osteoblast)
  • CDH13 - T-cadherin - H-cadherin (heart)
  • CDH15 - M-cadherin (myotubule)
  • CDH16 - KSP-cadherin
  • CDH17 - LI cadherin (liver-intestine)
  • CDH18 - cadherin 18, type 2
  • CDH19 - cadherin 19, type 2
  • CDH20 - cadherin 20, type 2
  • CDH23 - cadherin 23, (neurosensory epithelium)
  • CDH10; CDH11; CDH13; CDH15; CDH16; CDH17;

CDH18; CDH19; CDH20; CDH22; CDH23; CDH24; CDH26; CDH28; CDH4; CDH5; CDH6; CDH7; CDH8; CDH9;

CELSR1; CELSR2; CELSR3; CLSTN1; CLSTN2; CLSTN3; DCHS1; DCHS2; LOC389118;

See also

References

  1. ^ Hulpiau P, van Roy F (February 2009). "Molecular evolution of the cadherin superfamily". Int. J. Biochem. Cell Biol. 41 (2): 349–69. doi:10.1016/j.biocel.2008.09.027. PMID 18848899.
  2. ^ Angst B, Marcozzi C, Magee A (February 2001). "The cadherin superfamily: diversity in form and function". J Cell Sci. 114 (Pt 4): 629–41. PMID 11171368.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Bello, S.M.; Millo, H.; Rajebhosale, M.; Price, S.R. (2012). "Catenin-dependent cadherin function drives divisional segregation of spinal chord motor neurons". J. Neuroscience. 32 (2): 490–505. doi:10.1523/jneurosci.4382-11.2012.
  4. ^ Duguay, D.; A. Foty R., RA; S. Steinberg M., MS (2003). "Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants". Dev. Biol. 253 (2): 309–323. doi:10.1016/S0012-1606(02)00016-7. PMID 12645933.
  5. ^ Niessen, Carien M.; Gumbiner, Barry M. (2002). "Cadherin-mediated cell sorting not determined by binding or adhesion specificity". The Journal of Cell Biology. 156 (2): 389–399. doi:10.1083/jcb.200108040. PMC 2199232. PMID 11790800.
  6. ^ Volk, T.; Cohen, O.; Geiger, B. (1987). "Formation of heterotypic adherens-type junctions between L-CAM containing liver cells and A-CAM containing lens cells". Cell. 50 (6): 987–994. doi:10.1016/0092-8674(87)90525-3. PMID 3621349.
  7. ^ Bayas, Marco V.; Leung, Andrew; Evans, Evan; Leckband, Deborah (2005). "Lifetime Measurements Reveal Kinetic Differences between Homophilic Cadherin Bonds". Biophysical Journal. 90 (4): 1385–95. doi:10.1529/biophysj.105.069583. PMC 1367289. PMID 16326909.
  8. ^ Harris, Tony J.C., and Ulrich Tepass. "Adherins Junctions: From Molecules to Morphogenesis" Nature Reviews Molecular Cell Biology. 502-514. July 2010. doi:10.1038/nrm2927
  9. ^ a b Tepass, Ulrich, et al. "Cadherins in Embryonic and Neural Morphogenisis" Nature Reviews Molecular Cell Biology. November 2000.
  10. ^ Gumbiner, Barry M. "Regulation of Cadherin-Mediated Adhesion in Morphogenesis" Nature Reviews Molecular Cell Biology. 622-634. August 2005.
  11. ^ Reinhold, WC; Reimers, MA; Maunakea, AK; Kim, S; Lababidi, S; Scherf, U; Shankavaram, UT; Ziegler, MS; Stewart, C; Kouros-Mehr, Hosein; Cui, H; Dolginow, D; Scudiero, DA; Pommier, YG; Munroe, DJ; Feinberg, AP; Weinstein, JN (Feb 2007). "Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells". Molecular cancer therapeutics. 6 (2): 391–403. doi:10.1158/1535-7163.MCT-06-0609. PMID 17272646.
  12. ^ Beavon, IR (August 2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". European journal of cancer (Oxford, England : 1990). 36 (13 Spec No): 1607–20. PMID 10959047. Retrieved 17 November 2015.
  13. ^ PDB: 3Q2V​; Harrison, O.J., Jin, X., Hong, S., Bahna, F., Ahlsen, G., Brasch, J., Wu, Y., Vendome, J., Felsovalyi, K., Hampton, C.M., Troyanovsky, R.B., Ben-Shaul, A., Frank, J., Troyanovsky, S.M., Shapiro, L., Honig, B. (2011). "The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins". Structure. 19 (2): 244–56. doi:10.1016/j.str.2010.11.016. PMC 3070544. PMID 21300292.{{cite journal}}: CS1 maint: multiple names: authors list (link); rendered with PyMOL
  14. ^ Stefan Offermanns; Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. pp. 306–. ISBN 978-3-540-38916-3. Retrieved 14 December 2010.
  15. ^ a b Lodish, Harvey; Berk, Arnold; Kaiser, Chris; Krieger, Monte; Bretscher, Anthony; Ploegh, Hidde; Amon, Angelika (2013). Molecular Cell Biology (Seventh edition. ed.). New York: Worth Publ. p. 934. ISBN 978-1-4292-3413-9.

Further reading

Template:PBB Further reading

  • Renaud-Young M, Gallin WJ (2002). "In the first extracellular domain of E-cadherin, heterophilic interactions, but not the conserved His-Ala-Val motif, are required for adhesion". Journal of Biological Chemistry. 277 (42): 39609–39616. doi:10.1074/jbc.M201256200. PMID 12154084.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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