Structural Basis of the Tensile Strength of Protein Complexes Mediating Cell Adhesion

This study explores the behaviour of adhesive complexes of cell adhesion molecules undergoing forced detachment. Molecular-forces measurements combined with Steered Molecular Dynamic (SMD) simulations were used to investigate the mechanical response of the CD2 C58 and hemophilic C-cadherin bonds. The CD2-CD58 adhesive complex, important for the adaptive immune response, contains several salt-bridges in the adhesive interface. SMD simulations showed that these inter-protein salt bridges contribute independently to the tensile strength of the complex. Consistent with this, force measurements with the Surface Force Apparatus (SFA) demonstrated that the elimination of single salt bridges weakens the bond. The corresponding loss in adhesion energy of the CD2-CD58 complex correlates with the importance of the salt bridges observed in the simulations. These findings correlate closely with the effect of the elimination of single salt bridges observed in cell aggregation assays and binding measurements. On the other hand, the hemophilic C-cadherin interaction determines specific cell-cell adhesion during development in Xenopus laevis . Single molecule force spectroscopy was used to characterize the multiple bound states between C-cadherin ectodomains. The experiments showed two short-lived bound states associated with the two outermost ectodomains and two long-lived states associated with the full ectodomain. It is likely that the two short-lived states are involved in the specificity of the interaction since previous studies showed that the corresponding states in E-cadherin have different lifetimes. In addition, SMD simulations of the forced dissociation of the strand dieter of C-cadherin suggested a mechanism for the specificity of cadherin interactions.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics and Computational Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Bayas, Marco Vinicio

Contributors dc:contributor

• Deborah Leckband

• Physics, Molecular

Language dc:language

eng

Identifier

(MiAaPQ)AAI3198923

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/85446