title: New Insights into the Molecular Mechanism of E-Cadherin-Mediated Cell Adhesion by Free Energy Calculations.
abstract: Three-dimensional domain swapping is an important mode of protein association leading to the formation of stable dimers. Monomers associating via this mechanism mutually exchange a domain to form a homodimer. Classical cadherins, an increasingly important target for anticancer therapy, use domain swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic simulations, we reconstruct its conformational free energy landscape, obtaining the free energy profile connecting the inactive and active form. Our simulations predict that the E-cadherin monomer populates the open and closed forms almost equally, which is in agreement with the proposed "selected fit" mechanism in which monomers in an active conformational state bind to form a homodimer, analogous to the conformational selection mechanism often observed in ligand-target binding. Moreover, we find that the open state population is increased in the presence of calcium ions at the extracellular boundary, suggesting their possible role as allosteric activators of the conformational change.
authors.affiliation: Department of Chemistry, University of Milan , Via Camillo Golgi 19, Milan I-20133, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Doro
authors.affiliation: Department of Chemistry and Institute of Structural and Molecular Biology, University College London , 20 Gordon Street, London WC1H 0AJ, United Kingdom.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Saladino
authors.affiliation: Department of Chemistry, University of Milan , Via Camillo Golgi 19, Milan I-20133, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.affiliation: Department of Chemistry, University of Milan , Via Camillo Golgi 19, Milan I-20133, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Civera
authors.affiliation: Department of Chemistry and Institute of Structural and Molecular Biology, University College London , 20 Gordon Street, London WC1H 0AJ, United Kingdom.
authors.forename: Francesco L
authors.initials: FL
authors.lastname: Gervasio
mesh_terms: D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism; D002118:Calcium / Q000737:chemistry; D002448:Cell Adhesion / Q000502:physiology*; D019281:Dimerization; D007477:Ions / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D015820:Cadherins; D007477:Ions; D002118:Calcium