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Cadherin Edit Wikipedia article
|This article needs additional citations for verification. (December 2008)|
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.
The cadherin superfamily includes cadherins, protocadherins, desmogleins, and desmocollins, and more. 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. 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. In addition, several groups have observed heterotypic binding affinity (i.e., binding of different types of cadherin together) in various assays. 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.
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. These polypeptides are approximately 720â€“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 80 types of cadherins in humans have been identified and sequenced.
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. 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. Regulation of cadherin expression can occur through promoter methylation among other epigenetic mechanisms.
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. 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.
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.
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
- 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)
- Hulpiau P, van Roy F (February 2009). "Molecular evolution of the cadherin superfamily". Int. J. Biochem. Cell Biol. 41 (2): 349â€“69. doi:10.1016/j.biocel.2008.09.027. PMID 18848899.
- Angst B, Marcozzi C, Magee A (February 2001). "The cadherin superfamily: diversity in form and function". J Cell Sci 114 (Pt 4): 629â€“41. PMID 11171368.
- 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): 490â€“505. doi:10.1523/jneurosci.4382-11.2012.
- 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): 309â€“323. doi:10.1016/S0012-1606(02)00016-7. PMID 12645933.
- 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): 389â€“399. doi:10.1083/jcb.200108040. PMC 2199232. PMID 11790800.
- 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): 987â€“994. doi:10.1016/0092-8674(87)90525-3. PMID 3621349.
- Bayas, Marco V.; Leung, Andrew; Evans, Evan; Leckband, Deborah (2005). "Lifetime Measurements Reveal Kinetic Differences between Homophilic Cadherin Bonds". Biophysical Journal 90 (4): 1385â€“95. doi:10.1529/biophysj.105.069583. PMC 1367289. PMID 16326909.
- 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
- Tepass, Ulrich, et al. "Cadherins in Embryonic and Neural Morphogenisis" Nature Reviews Molecular Cell Biology. November 2000.
- Gumbiner, Barry M. "Regulation of Cadherin-Mediated Adhesion in Morphogenesis" Nature Reviews Molecular Cell Biology. 622-634. August 2005.
- 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): 391â€“403. doi:10.1158/1535-7163.MCT-06-0609. PMID 17272646.
- 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): 244â€“56. doi:10.1016/j.str.2010.11.016. PMC 3070544. PMID 21300292.; rendered with PyMOL
- Stefan Offermanns; Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. pp. 306â€“. ISBN 978-3-540-38916-3. Retrieved 14 December 2010.
- 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.
- Beavon IR (2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". Eur. J. Cancer 36 (13 Spec No): 1607â€“20. doi:10.1016/S0959-8049(00)00158-1. PMID 10959047.
- Berx G, Becker KF, HÃ¶fler H, van Roy F (1998). "Mutations of the human E-cadherin (CDH1) gene". Hum. Mutat. 12 (4): 226â€“37. doi:10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D. PMID 9744472.
- Bryant DM, Stow JL (2005). "The ins and outs of E-cadherin trafficking". Trends Cell Biol. 14 (8): 427â€“34. doi:10.1016/j.tcb.2004.07.007. PMID 15308209.
- Chun YS, Lindor NM, Smyrk TC et al. (2001). "Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated?". Cancer 92 (1): 181â€“7. doi:10.1002/1097-0142(20010701)92:1<181::AID-CNCR1307>3.0.CO;2-J. PMID 11443625.
- Georgolios A, Batistatou A, Manolopoulos L, Charalabopoulos K (2006). "Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC)". J. Exp. Clin. Cancer Res. 25 (1): 5â€“14. PMID 16761612.
- Hazan RB, Qiao R, Keren R et al. (2004). "Cadherin switch in tumor progression". Ann. N. Y. Acad. Sci. 1014 (1): 155â€“63. doi:10.1196/annals.1294.016. PMID 15153430.
- Moran CJ, Joyce M, McAnena OJ (2005). "CDH1 associated gastric cancer: a report of a family and review of the literature". Eur J Surg Oncol 31 (3): 259â€“64. doi:10.1016/j.ejso.2004.12.010. PMID 15780560.
- Reynolds AB, Carnahan RH (2005). "Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer". Semin. Cell Dev. Biol. 15 (6): 657â€“63. doi:10.1016/j.semcdb.2004.09.003. PMID 15561585.
- Wang HD, Ren J, Zhang L (2004). "CDH1 germline mutation in hereditary gastric carcinoma". World J. Gastroenterol. 10 (21): 3088â€“93. PMID 15457549.
- Wijnhoven BP, Dinjens WN, Pignatelli M (2000). "E-cadherin-catenin cell-cell adhesion complex and human cancer". The British journal of surgery 87 (8): 992â€“1005. doi:10.1046/j.1365-2168.2000.01513.x. PMID 10931041.
- Wilson PD (2001). "Polycystin: new aspects of structure, function, and regulation". J. Am. Soc. Nephrol. 12 (4): 834â€“45. PMID 11274246.
- 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): 39609â€“39616. doi:10.1074/jbc.M201256200. PMID 12154084.
- Proteopedia Cadherin - view cadherin structure in interactive 3D
- Cadherin domain in PROSITE
- The cadherin family
- Alberts, Bruce. Molecular Biology of the Cell
- The Cadherin Resource
- "Cadherin adhesome at a glance". J Cell Sci 126, 373-378
Cadherin-like Provide feedback
This cadherin domain is usually the most N-terminal copy of the domain.
Elledge HM, Kazmierczak P, Clark P, Joseph JS, Kolatkar A, Kuhn P, Muller U;, Proc Natl Acad Sci U S A. 2010;107:10708-10712.: Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members. PUBMED:20498078 EPMC:20498078
Trivedi M, Laurence JS, Williams TD, Middaugh CR, Siahaan TJ;, Int J Pharm. 2012;431:16-25.: Improving the stability of the EC1 domain of E-cadherin by thiol alkylation of the cysteine residue. PUBMED:22531851 EPMC:22531851
Internal database links
|SCOOP:||Cadherin_pro Cadherin_3 DUF4958|
|Similarity to PfamA using HHSearch:||Cadherin|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR013164
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 [PUBMED:2197976, PUBMED:,PUBMED: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 [PUBMED: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.
This entry represents a cadherin domain that is usually found at the N terminus of cadherin proteins.
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
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This clan includes a diverse range of domains that have an Ig-like fold and appear to be distantly related to each other. The clan includes: PKD domains, cadherins and several families of bacterial Ig-like domains as well as viral tail fibre proteins. it also includes several Fibronectin type III domain-containing families.
The clan contains the following 76 members:A2M_N Alpha_adaptinC2 Arch_flagellin Big_1 Big_2 Big_3 Big_3_2 Big_3_3 Big_3_4 Big_3_5 Big_4 Big_5 BiPBP_C BsuPI Cadherin Cadherin-like Cadherin_2 Cadherin_3 Cadherin_pro CARDB CBM39 CHB_HEX_C CHB_HEX_C_1 ChitinaseA_N CHU_C Coatamer_beta_C COP-gamma_platf CopC DUF11 DUF2271 DUF3244 DUF4165 DUF4625 DUF5011 DUF916 EpoR_lig-bind Filamin FixG_C FlgD_ig fn3 Fn3-like fn3_2 fn3_4 fn3_5 Fn3_assoc He_PIG HYR IFNGR1 IL17R_fnIII_D2 IL6Ra-bind Integrin_alpha2 Interfer-bind Invasin_D3 LEA_2 MG1 Mo-co_dimer Neurexophilin NPCBM_assoc PhoD_N PKD PKD_2 PKD_3 Pur_ac_phosph_N Qn_am_d_aIII REJ RHD_dimer Rib SoxZ SprB SWM_repeat T2SS-T3SS_pil_N TIG Tissue_fac Transglut_C TRAP_beta Y_Y_Y
We make a range of alignments for each Pfam-A family:
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- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
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Curation and family details
|Seed source:||Pfam-B_179 (release 17.0)|
|Number in seed:||64|
|Number in full:||2908|
|Average length of the domain:||82.60 aa|
|Average identity of full alignment:||38 %|
|Average coverage of the sequence by the domain:||9.40 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Cadherin_2 domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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