8.A.204.  The Cadherin (CDH) Family 

Cadherins are calcium-dependent cell adhesion proteins (Meigs et al. 2002). They preferentially interact with themselves in a homophilic manner to connect cells; cadherins may contribute to the sorting of heterogeneous cell types. CDH1 (E-canherin) is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells (Meigs et al. 2002). They have a potent invasive suppressor role and are ligands for integrin alpha-E/beta-7. E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors and has a strong inhibitory effect on APP C99 and C83 production. It serves as a receptor for Listeria monocytogenes; internalin A (InlA) binds to this protein and promotes uptake of the bacteria. Desmosomes are protein assemblies that mediate cell-cell adhesion and are prevalent in tissues under mechanical stress, such as heart and epithelial tissues (Pasani et al. 2023). These authors characterized the molecular architecture of the desmosomal outer dense plaque (ODP), and a validated model of the desmosomal ODP provided mechanistic insight into the function and assembly of desmosomes in normal and disease states (Pasani et al. 2023).

The function and structure of the mammalian epithelial cell layer is maintained by distinct intercellular adhesion complexes including adherens junctions (AJs), tight junctions, and desmosomes. The AJ is most integral for stabilizing cell-cell adhesion and conserving the structural integrity of epithelial tissues. AJs are comprised of the transmembrane protein E-cadherin and cytoplasmic catenin cofactors (alpha, beta, gamma, and p120-catenin) (Lessey et al. 2022). One organ where malfunction of AJ is a major contributor to disease states is the mammalian intestine. In the intestine, cell-cell adhesion complexes work synergistically to maintain structural integrity and homeostasis of the epithelium and prevent its malfunction. Consequently, when AJ integrity is compromised in the intestinal epithelium, the ensuing homeostatic disruption leads to diseases such as inflammatory bowel disease and colorectal carcinoma. In addition to their function at the plasma membrane, protein components of AJs have nuclear functions and are implicated in regulating gene expression and intracellular signaling. Within the nucleus, AJ proteins interact with transcription factors such as TCF/LEF and Kaiso (ZBTB33), which converge on the canonical Wnt signaling pathway. The multifaceted nature of AJ proteins highlights their complexity in modulating homeostasis and emphasizes the importance of their subcellular localization and expression in the mammalian intestine (Lessey et al. 2022).


 

References:

Hegazy, M., J.L. Koetsier, A.L. Huffine, J.A. Broussard, B.M. Godsel, E. Cohen-Barak, E. Sprecher, D.J. Wolfgeher, S.J. Kron, L.M. Godsel, and K.J. Green. (2022). Epidermal stratification requires retromer-mediated desmoglein-1 recycling. Dev Cell 57: 2683-2698.e8.

Lessey, L.R., S.C. Robinson, R. Chaudhary, and J.M. Daniel. (2022). Adherens junction proteins on the move-From the membrane to the nucleus in intestinal diseases. Front Cell Dev Biol 10: 998373.

Meigs, T.E., M. Fedor-Chaiken, D.D. Kaplan, R. Brackenbury, and P.J. Casey. (2002). Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J. Biol. Chem. 277: 24594-24600.

Paranjpe, I., P. Jayaraman, C.Y. Su, S. Zhou, S. Chen, R. Thompson, D.M. Del Valle, E. Kenigsberg, S. Zhao, S. Jaladanki, K. Chaudhary, S. Ascolillo, A. Vaid, E. Gonzalez-Kozlova, J. Kauffman, A. Kumar, M. Paranjpe, R.O. Hagan, S. Kamat, F.F. Gulamali, H. Xie, J. Harris, M. Patel, K. Argueta, C. Batchelor, K. Nie, S. Dellepiane, L. Scott, M.A. Levin, J.C. He, M. Suarez-Farinas, S.G. Coca, L. Chan, E.U. Azeloglu, E. Schadt, N. Beckmann, S. Gnjatic, M. Merad, S. Kim-Schulze, B. Richards, B.S. Glicksberg, A.W. Charney, and G.N. Nadkarni. (2023). Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection. Commun Med (Lond) 3: 81.

Pasani, S., K.S. Menon, and S. Viswanath. (2023). The molecular architecture of the desmosomal outer dense plaque by integrative structural modeling. bioRxiv.

Pohl, G.M., M. Göz, A. Gaertner, A. Brodehl, T. Cimen, A.M. Saguner, E. Schulze-Bahr, V. Walhorn, D. Anselmetti, and H. Milting. (2023). Cardiomyopathy related desmocollin-2 prodomain variants affect the intracellular cadherin transport and processing. Front Cardiovasc Med 10: 1127261.

Zhang, Y., Z. Yang, L. Song, Y. Li, and Q. Lin. (2024). Novel nanoparticle AuNCs conjugated with Desmoglein-3 antibody for FL/CT dual-mode targeted imaging and precise treatment of lung squamous cell carcinoma. J Colloid Interface Sci 659: 1003-1014.

Examples:

TC#NameOrganismal TypeExample
8.A.204.1.1

E-cadherin of 882 aas and probably 2 TMSs, one N-terminal and one near the C-terminus of the protein.  It shuffles between the plasma membrane and the nuclear membrane (Lessey et al. 2022).

CDH-1 of Homo sapiens

 
8.A.204.1.2

Cadherin-22 isoform X1 of 856 aas and probably two TMSs, one N-terminal and one near the C-terminus (residues 665 to 685).

CADH of Mauremys reevesii (Reeves's turtle)

 
8.A.204.1.3

Desmoglein-1 of 1050 aas and 2 TMSs, one N-terminal and one at residues 550 - 570. Epidermal stratification requires retromer-mediated desmoglein-1 recycling (Hegazy et al. 2022).

Desmoglein-1 of Equus asinus (ass)

 
8.A.204.1.4

Cadherin-like protein 26 of 825 aas with two TMSs, one N-terminal and one at residues 595 - 615.

CDH26 of Girardinichthys multiradiatus

 
8.A.204.1.5

Desmocollin-2, DSC2, of 901 aas with two TMSs, one N-terminal and the other at residue position 710.  It is a component of intercellular desmosome junctions and is involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. It may contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms. It is alterred in amounts following acute kidney injury following Covid-19 infection (Paranjpe et al. 2023). In addition to other members of family 8.A.204, it contains a domain homologous to those in cadherin (TC# 9.A.14.6.4) and protocadherin (TC# 1.A.17.4.13). Cardiomyopathy-related desmocollin-2 prodomain variants affect the intracellular cadherin transport and processing (Pohl et al. 2023).

Desmocollin-2 of Homo sapiens

 
8.A.204.1.6

Cadherin-18, CDH18, isoform 1 preproprotein of 790 aas and 2 TMSs, one N-terminal and one at residues 620 - 645. Celiac disease (CD) is a complex immune disease that affects duodenal mucosa, and CDH18 is present in lower amounts in diseased people.

CDH18 of Homo sapiens

 
8.A.204.1.7

Desmoglein-3, Dsg3 (CDHF6) of 999 aas.  It is a omponent of intercellular desmosome junctions and is involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.  Gold nanoclusters (AuNCs) conjugated with Dsg-3 antibodies form Au-Dsg-3 through a coupling reaction (Zhang et al. 2024).