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Strengthening E-cadherin adhesion via antibody-mediated binding stabilization

Bin Xie1, Shipeng Xu2, Leslayann Schecterson3

  • 1Biophysics Graduate Group, University of California, Davis, Davis, CA, USA.

Structure (London, England : 1993)
|December 5, 2023
PubMed

Insights

The monoclonal antibody 66E8 strengthens E-cadherin (Ecads) cell adhesion by stabilizing its key binding structure. This mechanism offers potential for new cancer metastasis therapies.

Area of Science:

  • Cell adhesion biology
  • Biophysics
  • Cancer research

Background:

  • E-cadherins (Ecads) are vital cell-cell adhesion proteins with tumor suppressor roles.
  • Enhanced Ecad adhesion via the 66E8 antibody may inhibit cancer metastasis.
  • The biophysical mechanisms of 66E8-mediated adhesion strengthening remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which the 66E8 antibody enhances E-cadherin binding.
  • To investigate how 66E8 stabilizes the E-cadherin adhesive conformation.

Main Methods:

  • Molecular dynamics simulations
  • Site-directed mutagenesis
  • Single-molecule atomic force microscopy (AFM)

Main Results:

  • The 66E8 antibody stabilizes the E-cadherin strand-swap dimer, the primary adhesive conformation.
  • Electrostatic interactions between 66E8 and Ecad stabilize the swapped β-strand and hydrophobic pocket.
  • 66E8 binding impedes conformational changes required for dimer rupture.

Conclusions:

  • The 66E8 antibody strengthens Ecad binding by stabilizing the strand-swap dimer.
  • This stabilization involves electrostatic interactions and prevention of conformational changes.
  • Findings provide mechanistic insights for antibody-mediated enhancement of cell adhesion.
Keywords:
66E8E-cadherinadhesion activating antibodiesallosterycell-cell adhesionconformation stabilizationrational design of adhesion strengthening antibodiesstrand-swap dimer

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