Schumann-Gillett Alexandra, Mark Alan E, Deplazes Evelyne, O'Mara Megan L
School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD, 4072, Australia.
Research School of Chemistry (RSC), The Australian National University, Canberra, ACT, 2061, Australia.
Eur Biophys J. 2018 Jan;47(1):59-67. doi: 10.1007/s00249-017-1229-3. Epub 2017 Jun 15.
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.
E-钙黏蛋白是一种跨膜糖蛋白，可促进上皮细胞间的黏附。天然结构的胞外结构域由五个重复的免疫球蛋白样结构域组成。所有E-钙黏蛋白晶体结构均显示该蛋白处于三种替代构象之一：单体、链交换反式同型二聚体和所谓的X-二聚体，后者被认为是形成链交换反式同型二聚体的动力学中间体。然而，先前的研究表明，即使一旦形成反式链交换二聚体，该复合物仍具有高度动态性，且E-钙黏蛋白单体可能会相对彼此重新定向。在此，分子动力学模拟已被用于研究人E-钙黏蛋白反式链交换二聚体的稳定性和构象灵活性。在四个独立的100纳秒模拟中，二聚体从起始结构移开并收敛到一种先前未报道的结构，我们将其称为Y-二聚体。Y-二聚体在总模拟时间的90%以上都存在，这表明它代表了溶液中E-钙黏蛋白二聚体的一种稳定构象。Y-二聚体构象通过反式链交换二聚体和X-二聚体晶体结构中存在的相互作用以及在任何E-钙黏蛋白二聚体晶体结构中均未发现的其他相互作用而得以稳定。Y-二聚体代表了人E-钙黏蛋白反式链交换二聚体一种先前未报道的稳定构象，并表明现有的晶体结构并未完全捕捉到人E-钙黏蛋白反式同型二聚体在溶液中所采用的构象。
