| Structural highlights
Disease
[PLAK_HUMAN] Defects in JUP are the cause of Naxos disease (NXD) [MIM:601214]. NXD is an autosomal recessive disorder combining diffuse non-epidermolytic palmoplantar keratoderma with arrhythmogenic right ventricular dysplasia/cardiomyopathy and woolly hair.[1] Defects in JUP are the cause of familial arrhythmogenic right ventricular dysplasia type 12 (ARVD12) [MIM:611528]; also called arrhythmogenic right ventricular cardiomyopathy 12 (ARVC12). ARVD is an autosomal dominant disease characterized by partial degeneration of the myocardium of the right ventricle, electrical instability, and sudden death. It is clinically defined by electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular free wall.[2] [3] [4]
Function
[PLAK_HUMAN] Common junctional plaque protein. The membrane-associated plaques are architectural elements in an important strategic position to influence the arrangement and function of both the cytoskeleton and the cells within the tissue. The presence of plakoglobin in both the desmosomes and in the intermediate junctions suggests that it plays a central role in the structure and function of submembranous plaques. Acts as a substrate for VE-PTP and is required by it to stimulate VE-cadherin function in endothelial cells. Can replace beta-catenin in E-cadherin/catenin adhesion complexes which are proposed to couple cadherins to the actin cytoskeleton (By similarity). [CADH1_MOUSE] Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7 (By similarity). E-Cad/CTF2 promotes non-amyloidogenic degradation of Abeta precursors. Has a strong inhibitory effect on APP C99 and C83 production (By similarity).
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Plakoglobin and beta-catenin are homologous armadillo repeat proteins found in adherens junctions, where they interact with the cytoplasmic domain of classical cadherins and with alpha-catenin. Plakoglobin, but normally not beta-catenin, is also a structural constituent of desmosomes, where it binds to the cytoplasmic domains of the desmosomal cadherins, desmogleins and desmocollins. Here, we report structural, biophysical, and biochemical studies aimed at understanding the molecular basis of selective exclusion of beta-catenin and alpha-catenin from desmosomes. The crystal structure of the plakoglobin armadillo domain bound to phosphorylated E-cadherin shows virtually identical interactions to those observed between beta-catenin and E-cadherin. Trypsin sensitivity experiments indicate that the plakoglobin arm domain by itself is more flexible than that of beta-catenin. Binding of plakoglobin and beta-catenin to the intracellular regions of E-cadherin, desmoglein1, and desmocollin1 was measured by isothermal titration calorimetry. Plakoglobin and beta-catenin bind strongly and with similar thermodynamic parameters to E-cadherin. In contrast, beta-catenin binds to desmoglein-1 more weakly than does plakoglobin. beta-Catenin and plakoglobin bind with similar weak affinities to desmocollin-1. Full affinity binding of desmoglein-1 requires sequences C-terminal to the region homologous to the catenin-binding domain of classical cadherins. Although pulldown assays suggest that the presence of N- and C-terminal beta-catenin "tails" that flank the armadillo repeat region reduces the affinity for desmosomal cadherins, calorimetric measurements show no significant effects of the tails on binding to the cadherins. Using purified proteins, we show that desmosomal cadherins and alpha-catenin compete directly for binding to plakoglobin, consistent with the absence of alpha-catenin in desmosomes.
Interactions of plakoglobin and beta-catenin with desmosomal cadherins: basis of selective exclusion of alpha- and beta-catenin from desmosomes.,Choi HJ, Gross JC, Pokutta S, Weis WI J Biol Chem. 2009 Nov 13;284(46):31776-88. Epub 2009 Sep 16. PMID:19759396[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, McKenna WJ. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000 Jun 17;355(9221):2119-24. PMID:10902626 doi:10.1016/S0140-6736(00)02379-5
- ↑ McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, McKenna WJ. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000 Jun 17;355(9221):2119-24. PMID:10902626 doi:10.1016/S0140-6736(00)02379-5
- ↑ Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ. A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2007 Nov;81(5):964-73. Epub 2007 Sep 28. PMID:17924338 doi:10.1086/521633
- ↑ den Haan AD, Tan BY, Zikusoka MN, Llado LI, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell SD, Bluemke DA, Calkins H, Dalal D, Judge DP. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. doi:, 10.1161/CIRCGENETICS.109.858217. Epub 2009 Jun 3. PMID:20031617 doi:10.1161/CIRCGENETICS.109.858217
- ↑ Choi HJ, Gross JC, Pokutta S, Weis WI. Interactions of plakoglobin and beta-catenin with desmosomal cadherins: basis of selective exclusion of alpha- and beta-catenin from desmosomes. J Biol Chem. 2009 Nov 13;284(46):31776-88. Epub 2009 Sep 16. PMID:19759396 doi:10.1074/jbc.M109.047928
|
