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Destabilization of the Epithelial Tissue Architecture by Competition with e-cadherin Homo-dimer formation: small molecule-induced disruption of the epithelium integrity and functions

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 Obiettivo del progetto (Objective)

'Cadherin expression on the surface of cells is critical for cell-cell adhesion and, consequently, for the development and the integrity of solid tissues. In mammals, impaired cadherin mediated adhesion has been implicated in all steps of tumor progression. E-cadherin, a prominent member of the cadherin family, is expressed on the surface of epithelial cells in the digestive tract, in the lungs as well as in the testis and other organs and is therefore responsible for the integrity of the mucosal tissues that protect a vast surface of the inner body. Cell adhesion mediated by E-cadherin and other type I cadherins involves homophilic “trans” interactions that are brought about by a strand exchange mechanism involving the N-terminal extracellular domain. The epithelial tissue constitutes the body’s first line of defense and, as such, is exposed to a large number of small, potentially toxic molecules from the environment whose chemical and structural features are reminiscent of the tryptophan residue (Trp2) used by E-cadherin in its dimerization mechanism. These molecules can mimic the Trp2 function in E-cadherin by inserting into the hydrophobic acceptor pocket of E-cadherin and by occuping the site of Trp2 docking, thus potentially interfering with the E-cadherin mechanism of self-adhesion. We hypothesize that such events can disrupt the integrity of the epithelial tissue, ultimately causing tissue remodeling and the loss of the epithelium’s protective properties. The main aim of this project is to use X-ray crystallographic analysis to determine whether a number of known environmental pollutants that are present in the atmosphere as well as in foods or other media to which the population is commonly exposed can bind into or in the vicinity of the E-cadherin hydrophobic pocket or cause structural changes that prevent E-cadherin dimerization, thus causing disruption in the integrity of the body’s first line of defense.'

Introduzione (Teaser)

Cell to cell adhesion is critical for the development and integrity of solid tissues. EU researchers investigated a family of molecules, the cadherins, which play a key role in ensuring that cells stick together to form stable tissues with well-defined mechanical properties.