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786  structures 929  species 0  interactions 278836  sequences 2360  architectures

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This is the Wikipedia entry entitled "Cadherin". More...

Principal interactions of structural proteins at cadherin-based adherens junction. Actin filaments are linked to Î±-actinin and to the membrane through vinculin. The head domain of vinculin is associated with E-cadherin via Î±-, Î²-, and Î³-catenins. The tail domain of vinculin binds to membrane lipids and to actin filaments.

The cadherin family is essential in maintaining the cell-cell contact and regulating cytoskeletal complexes. The cadherin superfamily includes cadherins, protocadherins, desmogleins, desmocollins, and more.[2][3] In structure, they share cadherin repeats, which are the extracellular Ca2+-binding domains. There are multiple classes of cadherin molecules, each designated with a prefix (in general, noting the types of tissue with which it is associated). Classical cadherins maintain the tone of tissues by forming a homodimer in cis while desmosomal cadherins are heterodimeric.[4] The intracellular portion of classical cadherins interacts with a complex of proteins that allows connection to the actin cytoskeleton. Although classical cadherins take a role in cell layer formation and structure formation, desmosomal cadherins focus on resisting cell damage. Desmosomal cadherins are responsible to maintain the function of desmosomes that is to overturn the mechanical stress of the tissues. Similar to classical cadherins, desmosomal cadherins has a single transmembrane domain, five EC repeats, and an intracellular domain. Two types of desmosomal cadherins exist, and they are called desmogleins and desmocollins that contains an intracellular anchor and cadherin like sequence (ICS). The adaptor proteins that associate with desmosomal cadherins are plakoglobin (related to ${\displaystyle \beta }$-catenin), plakophilins (p120 catenin subfamily), and desmoplakins. The major function of desmoplakins to bind to intermediate filament thorough interaction with plakoglobin that attaches to ICS of desmogleins and desmocollins and plakophilins. A[4] typical cadherins are different from other types of cadherins and consist of one or more extracellular repeat domains. The components that build an atypical cadherin are flamingo (seven pass transmembrane) and Dcad102F-like cadherins. Their job is to take part in signaling pathway instead of performing cell-cell adhesion.

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.[5] 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.[6] In addition, several groups have observed heterotypic binding affinity (i.e., binding of different types of cadherin together) in various assays.[7][8] 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.[9]

## Structure

Domain organization of different types of cadherins

Cadherins are synthesized as polypeptides and undergo many post-translational modifications to become the proteins which mediate cell-cell adhesion and recognition.[10] These polypeptides are approximately 720â€“750 amino acids long. Each cadherin has a small C-terminal cytoplasmic component, a transmembrane component, and the remaining bulk of the protein is extra-cellular (outside the cell). The transmembrane component consists of single chain glycoprotein repeats.[11] Â Because cadherins are Ca2+ dependent, they have five tandem extracellular domain repeats that act as the binding site for Ca2+ ions.[12] Â Their extracellular domain interacts with two separateÂ transÂ dimer conformations: strand-swap dimers (S-dimers) and X-dimers.[12] To date, over 100 types of cadherins in humans have been identified and sequenced.[13]

Â The functionality of cadherins relies upon the formation of two identical subunits, known as homodimers.[11] The homodimeric cadherins create cell-cell adhesion with cadherins present in the membranes of other cells through changing conformation from cis-dimers to trans-dimers.[11] Once the cell-cell adhesion between cadherins present in the cell membranes of two different cells has formed, adherens junctions can then be made when protein complexes, usually composed of Î±-, Î²-, and Î³-catenins, bind to the cytoplasmic portion of the cadherin.[11] Regulatory proteins include p-120 catenin, ${\displaystyle \alpha }$-catenin, Â ${\displaystyle \beta }$-catenin, and vinculin. Binding of p-120 catenin and ${\displaystyle \beta }$-catenin to the homodimer increases the stability of the classical cadherin. ${\displaystyle \alpha }$-catenin is engaged by p120-catenin complex, where vinculin is recruited to take a role in indirect association with actin cytoskeleton.[4] However, cadherin-catenin complex can also bind directly to the actin without the help of vinculin. Moreover, the strength of cadherin adhesion can increase by dephosphorylation of p120 catenin and the binding of ${\displaystyle \alpha }$-catenin and vinculin.

## Function

### Development

After development, cadherins play a role in maintaining cell and tissue structure, and in cellular movement.[13] Regulation of cadherin expression can occur through promoter methylation among other epigenetic mechanisms.[17]

### Tumour metastasis

The E-cadherinâ€“catenin complex plays a key role in cellular adhesion; loss of this function has been associated with increased invasiveness and metastasis of tumors.[18] The suppression of E-cadherin expression is regarded as one of the main molecular events responsible for dysfunction in cell-cell adhesion, which can lead to local invasion and ultimately tumor development. Because E-cadherins play an important role in tumor suppression, they are also referred to as the "suppressors of invasion".[19]

### Correlation to cancer

It has been discovered that cadherins and other additional factors are correlated to the formation and growth of some cancers and how a tumor continues to grow. The E-cadherins, known as the epithelial cadherins, are on the surface of one cell and can bind with those of the same kind on another to form bridges.[20] The loss of the cell adhesion molecules, E cadherins, is causally involved in the formation of epithelial types of cancers such as carcinomas. The changes in any types of cadherin expression may not only control tumor cell adhesion but also may affect signal transduction leading to the cancer cells growing uncontrollably.[21]

In epithelial cell cancers, disrupted cell to cell adhesion might lead to the development of secondary malignant growths; they are distant from the primary site of cancer and can result from the abnormalities in the expression of E-cadherins or its associated catenins. CAMs such as the cadherin glycoproteins that normally function as the glue and holds cells together act as important mediators of cell to cell interactions. E-cadherins, on the surface of all epithelial cells, are linked to the actin cytoskeleton through interactions with catenins in the cytoplasm. Thus, anchored to the cytoskeleton, E-cadherins on the surface of one cell can bind with those on another to form bridges. In epithelial cell cancers, disrupted cell-cell adhesion that might lead to metastases can result from abnormalities in the expression of E-cadherin or its associated catenins.[20]

## Correlation to endometrium and embryogenesis

This family of glycoproteins is responsible for calcium-dependent mechanism of intracellular adhesion. E-cadherins are crucial in embryogenesis during several processes, including gastrulation, neurulation, and organogenesis. Furthermore, suppression of E-cadherins impairs intracellular adhesion. The levels of these molecules increase during the luteal phase while their expression is regulated by progesterone with endometrial calcitonin.[22]

## Types

Ribbon representation of a repeating unit in the extracellular E-cadherin ectodomain of the mouse (â€‹) [23]
Identifiers
PfamPF00028
InterProIPR002126
SMARTCA
PROSITEPDOC00205
SCOP21nci / SCOPe / SUPFAM
Membranome114
See Pfam CL0159 for other Cadherin families.

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.[24][25] These large amount of diversities are accomplished by having multiple cadherin encoding genes combined with alternative RNA splicing mechanisms. Invertebrates contain fewer than 20 types of cadherins.[25]

### Classical

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

• CDH1 â€“ E-cadherin (epithelial): E-cadherins are found in epithelial tissue; not to be confused with the APC/C activator protein CDH1.

## References

1. ^ a b Alimperti S, Andreadis ST (May 2015). "CDH2 and CDH11 act as regulators of stem cell fate decisions". Stem Cell Research. 14 (3): 270â€“82. doi:10.1016/j.scr.2015.02.002. PMCÂ 4439315. PMIDÂ 25771201.
2. ^ Hulpiau P, van Roy F (February 2009). "Molecular evolution of the cadherin superfamily". The International Journal of Biochemistry & Cell Biology. 41 (2): 349â€“69. doi:10.1016/j.biocel.2008.09.027. PMIDÂ 18848899.
3. ^ Angst BD, Marcozzi C, Magee AI (February 2001). "The cadherin superfamily: diversity in form and function". Journal of Cell Science. 114 (Pt 4): 629â€“41. doi:10.1242/jcs.114.4.629. PMIDÂ 11171368.
4. ^ a b c Priest AV, Koirala R, Sivasankar S (December 2019). "Single-molecule studies of classical and desmosomal cadherin adhesion". Current Opinion in Biomedical Engineering. 12: 43â€“50. doi:10.1016/j.cobme.2019.08.006. PMCÂ 6859941. PMIDÂ 31742239.
5. ^ Bello SM, Millo H, Rajebhosale M, Price SR (January 2012). "Catenin-dependent cadherin function drives divisional segregation of spinal motor neurons". The Journal of Neuroscience. 32 (2): 490â€“505. doi:10.1523/jneurosci.4382-11.2012. PMCÂ 3292792. PMIDÂ 22238085.
6. ^ Duguay D, Foty RA, Steinberg MS (January 2003). "Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants". Developmental Biology. 253 (2): 309â€“23. doi:10.1016/S0012-1606(02)00016-7. PMIDÂ 12645933.
7. ^ Niessen CM, Gumbiner BM (January 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. PMCÂ 2199232. PMIDÂ 11790800.
8. ^ Volk T, Cohen O, Geiger B (September 1987). "Formation of heterotypic adherens-type junctions between L-CAM-containing liver cells and A-CAM-containing lens cells". Cell. 50 (6): 987â€“94. doi:10.1016/0092-8674(87)90525-3. PMIDÂ 3621349. S2CIDÂ 21428349.
9. ^ Bayas MV, Leung A, Evans E, Leckband D (February 2006). "Lifetime measurements reveal kinetic differences between homophilic cadherin bonds". Biophysical Journal. 90 (4): 1385â€“95. Bibcode:2006BpJ....90.1385B. doi:10.1529/biophysj.105.069583. PMCÂ 1367289. PMIDÂ 16326909.
10. ^ Harris TJ, Tepass U (July 2010). "Adherens junctions: from molecules to morphogenesis". Nature Reviews. Molecular Cell Biology. 11 (7): 502â€“14. doi:10.1038/nrm2927. PMIDÂ 20571587. S2CIDÂ 13638902.
11. ^ a b c d Marie PJ, HaÃ¿ E, Modrowski D, Revollo L, Mbalaviele G, Civitelli R (January 2014). "Cadherin-mediated cell-cell adhesion and signaling in the skeleton". Calcified Tissue International. 94 (1): 46â€“54. doi:10.1007/s00223-013-9733-7. PMCÂ 4272239. PMIDÂ 23657489.
12. ^ a b Priest AV, Shafraz O, Sivasankar S (September 2017). "Biophysical basis of cadherin mediated cell-cell adhesion". Experimental Cell Research. 358 (1): 10â€“13. doi:10.1016/j.yexcr.2017.03.015. PMIDÂ 28300566.
13. ^ a b Tepass U, Truong K, Godt D, Ikura M, Peifer M (November 2000). "Cadherins in embryonic and neural morphogenesis". Nature Reviews. Molecular Cell Biology. 1 (2): 91â€“100. doi:10.1038/35040042. PMIDÂ 11253370. S2CIDÂ 1632053.
14. ^ Gumbiner BM (August 2005). "Regulation of cadherin-mediated adhesion in morphogenesis". Nature Reviews. Molecular Cell Biology. 6 (8): 622â€“34. doi:10.1038/nrm1699. PMIDÂ 16025097. S2CIDÂ 25094246.
15. ^ a b c Taneyhill LA, Schiffmacher AT (June 2017). "Should I stay or should I go? Cadherin function and regulation in the neural crest". Genesis. 55 (6): e23028. doi:10.1002/dvg.23028. PMCÂ 5468476. PMIDÂ 28253541.
16. ^ a b Roy, Frans (2013). The Molecular Biology of Cadherins. Elsevier. pp.Â 264â€“274. ISBNÂ 978-0-12-394311-8.
17. ^ Reinhold WC, Reimers MA, Maunakea AK, Kim S, Lababidi S, Scherf U, etÂ al. (February 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. PMIDÂ 17272646.
18. ^ Beavon IR (August 2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". European Journal of Cancer. 36 (13 Spec No): 1607â€“20. doi:10.1016/S0959-8049(00)00158-1. PMIDÂ 10959047.
19. ^ Nives PeÄ‡ina-Å laus (2003). "Tumor suppressor gene E-cadherin and its role in normal and malignant cells". Cancer Cell Int. 3 (17): 17. doi:10.1186/1475-2867-3-17. PMCÂ 270068. PMIDÂ 14613514.
20. ^ a b Morales CP, Souza RF, Spechler SJ (November 2002). "Hallmarks of cancer progression in Barrett's oesophagus". Lancet. 360 (9345): 1587â€“9. doi:10.1016/S0140-6736(02)11569-8. PMIDÂ 12443613. S2CIDÂ 22401564.
21. ^ Cavallaro U, Schaffhauser B, Christofori G (February 2002). "Cadherins and the tumour progression: is it all in a switch?". Cancer Letters. 176 (2): 123â€“8. doi:10.1016/S0304-3835(01)00759-5. PMIDÂ 11804738.
22. ^ Grigorian IY, Linkova NS, Polyakova VO, Paltseva EM, Kozlov KL (January 2016). "Signaling molecules of the endometrium: Gerontological and general pathological aspects". Advances in Gerontology. 6 (1): 36â€“43. doi:10.1134/S2079057016010045. S2CIDÂ 87472683.
23. ^ Harrison OJ, Jin X, Hong S, Bahna F, Ahlsen G, Brasch J, etÂ al. (February 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. PMCÂ 3070544. PMIDÂ 21300292.
24. ^ Offermanns S, Rosenthal W (2008). Encyclopedia of Molecular Pharmacology. Springer. pp.Â 306â€“. ISBNÂ 978-3-540-38916-3. Retrieved 14 December 2010.
25. ^ a b Lodish H, Berk A, Kaiser C, Krieger M, Bretscher A, Ploegh H, Amon A (2013). Molecular Cell Biology (SeventhÂ ed.). New York: Worth Publ. p.Â 934. ISBNÂ 978-1-4292-3413-9.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

No Pfam abstract.

This tab holds annotation information from the InterPro database.

# InterPro entry IPR002126

Cadherins are a group of transmembrane proteins that serve as the major adhesion molecules located within adherens junctions. They can regulate cell-cell adhesion through their extracellular domain and their cytosolic domains connect to the actin cytoskeleton by binding to catenins [ PUBMED:25014356 ]. These proteins preferentially interact with themselves in a homophilic manner in connecting cells; thus acting as both receptor and ligand. 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.

This entry represents the extracellular repeated domains found in cadherins and related proteins.

### Gene Ontology

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# Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

# Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

## View options

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Seed
(55)
Full
(278836)
Representative proteomes UniProt
(455561)
RP15
(34606)
RP35
(87224)
RP55
(209664)
RP75
(284697)
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PP/heatmap 1

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

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## Format an alignment

Seed
(55)
Full
(278836)
Representative proteomes UniProt
(455561)
RP15
(34606)
RP35
(87224)
RP55
(209664)
RP75
(284697)
Alignment:
Format:
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Sequence:
Gaps:

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Seed
(55)
Full
(278836)
Representative proteomes UniProt
(455561)
RP15
(34606)
RP35
(87224)
RP55
(209664)
RP75
(284697)

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

# HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

# Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

# Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

## Curation

 Seed source: Swissprot_feature_table Previous IDs: cadherin; Type: Domain Sequence Ontology: SO:0000417 Author: Sonnhammer ELL Number in seed: 55 Number in full: 278836 Average length of the domain: 93.10 aa Average identity of full alignment: 25 % Average coverage of the sequence by the domain: 45.26 %

## HMM information

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 28.8 28.8
Trusted cut-off 28.8 28.8
Noise cut-off 28.7 28.7
Model length: 93
Family (HMM) version: 20

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# Structures

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 domain has been found. There are 786 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 sequence.

# AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

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