Degree Type

Dissertation

Date of Award

2016

Degree Name

Doctor of Philosophy

Department

Physics and Astronomy

Major

Physics

First Advisor

Sanjeevi Sivasankar

Abstract

Classical cadherins are Ca2+-dependent, transmembrane, cellular adhesion proteins that are essential for the development and maintenance of tissue structures. As cells sort and re-arrange to form functional tissues, these proteins are subjected to tugging forces. However, the mechanisms by which cadherins withstand mechanical forces and regulate their adhesion in response to mechanical stress is not understood at the molecular level. This dissertation integrates single molecule force clamp experiments using Atomic Force Microscope, molecular dynamics simulations, steered molecular dynamics simulations, principal component analysis and coarse-grained energy landscape mapping to understand, at the single molecule level, the mechanisms by which cadherins mediate cellular adhesion in the presence of tensile forces.

I show that cadherins can bind in multiple trans conformations: strand-swap dimers (S-dimers), X-dimers and an intermediate conformation sampled along the X-dimer to S-dimer interconversion pathway. These conformations respond to force by varying their biomechanical properties. S-dimers are in a binding orientation that form slip bonds that weaken as force increases. In contrast, when X-dimers are pulled, they rearrange themselves and form force-induced interactions that lock them into a tighter conformation that resists rupture. X-dimers thus form biphasic catch-slip bonds that initially strengthen with force and then weaken beyond a critical force. Finally, intermediate structure undergoes a torsional motion perpendicular to the pulling direction which results in ideal bonds that are insensitive to tensile stress. By varying their conformation, cadherins are thus able to tune their kinetics and withstand mechanical stress.

Copyright Owner

Kristine Manibog

Language

en

File Format

application/pdf

File Size

134 pages

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