The Desmoglein-Specific Cytoplasmic Region Is Intrinsically Disordered in Solution and Interacts with Multiple Desmosomal Protein Partners

Kami, Keiichiro; Chidgey, Martyn; Dafforn, Timothy R.; Overduin, Michael

doi:10.1016/j.jmb.2008.12.054

Cited by 24 publications

(19 citation statements)

References 59 publications

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“…Similarly unfavorable binding entropies are observed for the interaction of the homologous desmosomal cadherins with plakoglobin ( Table 2), suggesting that the equivalent regions of Dsg and Dsc are also intrinsically unstructured. Moreover, the desmoglein-specific cytoplasmic region required for full affinity is also an intrinsically unstructured protein (38). These observations are consistent with the abnormally large apparent molecular masses of these proteins on sizing columns (data not shown).…”

Section: Structure Of the Plakoglobin-e-cadherinsupporting

confidence: 79%

“…Dsg1-CBD binds with a slightly reduced affinity of 510 nM relative to the full domain. As shown in Table 2, extending the construct to residue 958, which includes most of the desmoglein-specific cytoplasmic region (38), restores full binding affinity. In contrast, a similar analysis of the desmocollin-1 cytoplasmic domain shows that the region of this protein homologous to the E-cadherin CBD binds to plakoglobin with the same affinity as the slightly larger full cytoplasmic domain.…”

Section: Structure Of the Plakoglobin-e-cadherinmentioning

confidence: 99%

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Interactions of Plakoglobin and β-Catenin with Desmosomal Cadherins

Choi

Gross

Pokutta

et al. 2009

Journal of Biological Chemistry

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Plakoglobin and ␤-catenin are homologous armadillo repeat proteins found in adherens junctions, where they interact with the cytoplasmic domain of classical cadherins and with ␣-catenin. Plakoglobin, but normally not ␤-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 ␤-catenin and ␣-catenin from desmosomes. The crystal structure of the plakoglobin armadillo domain bound to phosphorylated E-cadherin shows virtually identical interactions to those observed between ␤-catenin and E-cadherin. Trypsin sensitivity experiments indicate that the plakoglobin arm domain by itself is more flexible than that of ␤-catenin. Binding of plakoglobin and ␤-catenin to the intracellular regions of E-cadherin, desmoglein1, and desmocollin1 was measured by isothermal titration calorimetry. Plakoglobin and ␤-catenin bind strongly and with similar thermodynamic parameters to E-cadherin. In contrast, ␤-catenin binds to desmoglein-1 more weakly than does plakoglobin. ␤-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 ␤-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 ␣-catenin compete directly for binding to plakoglobin, consistent with the absence of ␣-catenin in desmosomes.Adherens junctions and desmosomes are two kinds of intercellular junctions that mediate strong attachments between adjacent cells and are essential for embryonic development and epithelial tissue differentiation (1-5). These junctions share a parallel architecture in which the extracellular regions of transmembrane cadherin cell adhesion proteins mediate cell-cell contacts, whereas the intracellular regions of cadherins associate with the underlying cytoskeleton (3, 4). Adherens junctions contain the classical cadherins, which are functionally linked to the actin-based cytoskeleton (1, 6). Desmosomal cadherins, in contrast, are linked to the intermediate filament system (2).In adherens junctions, the intracellular region of classical cadherins binds to the protein ␤-catenin or plakoglobin. ␤-Catenin binds strongly to the cytoplasmic domain of E-cadherin (E cyto ) 2 with a dissociation constant K D of 36 nM or 52 pM, depending on the phosphorylation state of E cyto (7). ␤-Catenin and plakoglobin bind to the F-actin-binding protein ␣-catenin (6). ␣-Catenin may have a role in linking the cadherin-␤-catenin complex to actin, but binding to ␤-catenin weakens the affinity of ␣-catenin fo...

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Section: Structure Of the Plakoglobin-e-cadherinsupporting

confidence: 79%

Section: Structure Of the Plakoglobin-e-cadherinmentioning

confidence: 99%

Interactions of Plakoglobin and β-Catenin with Desmosomal Cadherins

Choi

Gross

Pokutta

et al. 2009

Journal of Biological Chemistry

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“…Likewise, removal of these domains blunted the capacity of ectopic DSG1 to inhibit ERK signaling and promote differentiation. These data, and earlier work that identified DSG1 residue 888 as a caspase-3 cleavage site during UV-induced apoptosis, provide the first experimental evidence to our knowledge that the unique domains (PL, RUD, and TD) participate in epidermal signaling (81)(82)(83). In addition, a recent investigation of comparable domains in DSG2 indicates an important role in mediating homodimerization, internalization, and protein stability (84).…”

Section: Figuresupporting

confidence: 68%

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

Harmon

Simpson²,

Johnson³

et al. 2013

J. Clin. Invest.

131

158

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Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

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“…Biochemical data confi rmed these predictions. Specifi cally, desmoplakin anchored intermediate fi laments Kouklis et al, 1994;Bornslaeger et al, 1996;Meng et al, 1997); plakophilins, plakoglobin, and desmoplakin bound each other to form a plaque (Chen et Kowalczyk et al, 1997;Bornslaeger et al, 2001), and interactions mediated by plakoglobin and plakophilin linked the plaque-fi lament complex to transmembrane, desmogleins, and desmocollins (Smith & Fuchs, 1998;Chen et al, 2002;Bonne et al, 2003;Hatzfeld et al, 2000;Kami et al, 2009;Troyanovsky et al, 1994a, 1994b, Kowalczyk et al, 1996Witcher et al, 1996;Choi et al, 2009;Mathur et al, 1994;Roh & Stanley, 1995;Kowalczyk et al, 1999;Andl & Stanley, 2001;Bornslaeger et al, 2001;Gaudry et al, 2001). The ability of desmosomal cadherins to establish trans interactions between cells, in turn, accounted for the actual adhesive bond formed between two cells (Waschke et al, 2007;Nie et al, 2011;Chitaev & Troyanovsky, 1997;Aoyama et al, 2009).…”

Section: Assembly : Intradesmosomal Protein Interactionsmentioning

confidence: 99%