A potential new, stable state of the E-cadherin strand-swapped dimer in solution
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E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution.
KeywordsE-cadherin Homodimer Molecular dynamics Converged structure
Double electron–electron resonance
GROningen MAchine for Chemical Simulation
Protein Data Bank
Simple point charge
This work was supported by grants from the Australian Research Council (ARC) to AEM and MLO (DP130102153), and the Medical Advances Without Animals Trust (MAWA) to MLO, ED and ASG. ED is a NHMRC Early Career Research Fellow. This research was undertaken with the assistance of resources provided at the National Computational Infrastructure National Facility systems, housed at the Australian National University, through the National Computational Merit Allocation Scheme supported by the Australian Government.
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