Abstract
Human P-cadherin is a cell adhesion protein of the family of classical cadherins, the overexpression of which is correlated with poor prognosis in various types of cancer. Antibodies inhibiting cell-cell adhesion mediated by P-cadherin show clear therapeutic effect, although the mechanistic basis explaining their effectiveness is still unclear. Based on structural, physicochemical, and functional analyses, we have elucidated the molecular mechanism of disruption of cell adhesion by antibodies targeting human P-cadherin. Herein we have studied three different antibodies, TSP5, TSP7, and TSP11, each recognizing a different epitope on the surface of the cell-adhesive domain (EC1). Although all these three antibodies recognized human P-cadherin with high affinity, only TSP7 disrupted cell adhesion. Notably, we demonstrated that TSP7 abolishes cell adhesion by disabling the so-called X-dimer (a kinetic adhesive intermediate), in addition to disrupting the strand-swap dimer (the final thermodynamic state). The inhibition of the X-dimer was crucial for the overall inhibitory effect, raising the therapeutic value of a kinetic intermediary not only for preventing, but also for reversing, cell adhesion mediated by a member of the classical cadherin family. These findings should help to design more innovative and effective therapeutic solutions targeting human P-cadherin.
Highlights
IntroductionBeen elucidated at the molecular and cellular levels[19,20,21]
Been elucidated at the molecular and cellular levels[19,20,21]. In these studies we have showed that the so-called strand-swap dimer is the active cell adhesive species, in agreement with what has been reported for other classical cadherins
TSP7 and TSP11 recognized native P-cadherin molecules expressed on the cell surface (EC50 ≈ 1–5 nM) (Fig. 1b)
Summary
Been elucidated at the molecular and cellular levels[19,20,21] In these studies we have showed that the so-called strand-swap dimer is the active cell adhesive species, in agreement with what has been reported for other classical cadherins. Crystal structures of the complex between P-cadherin and two different antibodies revealed the structural basis of the antigen-antibody interaction, and why a particular antibody was effective at inhibiting the formation of the X-dimer species To our knowledge, this is the first report explaining the mechanism of disruption of cell adhesion of a classical cadherin at the molecular level. We anticipate our study will advance the design of novel antibody drugs targeting P-cadherin
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