Strengthening E-cadherin adhesion via antibody mediated binding stabilization

Area of Science:

• Biophysics
• Molecular Biology
• Cancer Research

Background:

• E-cadherins (Ecads) are vital cell-cell adhesion proteins with demonstrated tumor suppressor functions.
• Enhanced Ecad adhesion via the monoclonal antibody 66E8 shows promise for inhibiting cancer metastasis.
• The precise biophysical mechanisms behind 66E8-mediated adhesion strengthening remain unelucidated.

Approach:

• Employed molecular dynamics simulations to investigate protein interactions.
• Utilized site-directed mutagenesis to probe specific amino acid residues.
• Conducted single-molecule atomic force microscopy experiments to measure adhesion forces.

Key Points:

• 66E8 strengthens Ecad binding by stabilizing the primary adhesive conformation, the strand-swap dimer.
• Electrostatic interactions between 66E8 and Ecad stabilize the swapped β-strand and its hydrophobic pocket.
• The antibody impedes necessary conformational changes required for the rupture of the strand-swap dimer.

Conclusions:

• Identified fundamental mechanistic principles for antibody-mediated strengthening of E-cadherin binding.
• Provides insights into targeting cell-cell adhesion for cancer therapy.
• Establishes a framework for designing novel antibodies to modulate protein-protein interactions.