Remarkable disparity in mechanical response among the extracellular domains of type I and II cadherins

Abstract

Cadherins, a large family of calcium-dependent adhesion molecules, are critical for intercellular adhesion. While crystallographic structures for several cadherins show clear structural similarities, their relevant adhesive strengths vary and their mechanisms of adhesion between types I and II cadherin subfamilies are still unclear. Here, stretching of cadherins was explored experimentally by atomic force microscopy and computationally by steered molecular dynamics (SMD) simulations, where partial unfolding of the E-cadherin ectodomains was observed. The SMD simulations on strand-swapping cadherin dimers displayed similarity in binding strength, suggesting contributions of other mechanisms to explain the strength differences of cell adhesion in vivo. Systematic simulations on the unfolding of the extracellular domains of type I and II cadherins revealed diverse pathways. However, at the earliest stage, a remarkable similarity in unfolding was observed for the various type I cadherins that was distinct from that for type II cadherins. This likely correlates positively with their distinct adhesive properties, suggesting that the initial forced deformation in type I cadherins may be involved in cadherin-mediated adhesion.

An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:25

Keywords:

• classical type I cadherins
• classical type II cadherins
• E-cadherin
• cell adhesion
• homophilic interaction
• calcium bridge
• SMD simulation
• single-molecule force spectroscopy
• AFM force mode
• unfolding
• intermediate state
• conformational dynamics
• elasticity

Acknowledgements

We would like thank the Computer Center under the office of Deputy President and Center for Computational Science and Engineering at National University of Singapore for providing the computational service for simulations done in this paper. We gratefully acknowledge support from MechanoBiology Institute Seed grant (WBS R-714-002-007-271).