UCLA Chemistry & Biochemistry Distinguished Lecture Series

Thu, Jan 23 4:00pm
Speaker Barry Honig
Hosted by
UCLA Department of Chemistry and Biochemistry
Professor Miguel Garcia-Garibay
Sticking Together Like a Family:
The Molecular Basis of Cadherin-Mediated Cell-Cell Adhesion 
Professor Barry Honig
Howard Hughes Medical Institute, Center for Computational Biology and Bioinformatics, Department of Systems Biology and Department of Biochemistry and Molecular Biophysics, Columbia University, 1130 St. Nicholas Ave., New York, NY, 10032
A variety of cell-cell adhesion processes are mediated by the dimerization of cadherin proteins presented from apposing cell surfaces.  However a clear relationship between molecular and cellular properties has not been established.  A multi-scale combined experimental/theoretical approach to this general problem will be described. Specifically, crystal structures, biophysical measurements and simulations on wild-type and mutant proteins are used to determine the molecular basis of cadherin-cadherin interactions. The molecular basis of the finely tuned evolutionary design of differential homophilic and heterophilic binding affinities between closely related members of the same protein family will be described and a correlation will be established between measured binding affinities at the molecular level and cell-cell adhesive specificity.
The signaling activity of cadherins involves the lateral oligomerization of trans dimers formed between cadherins on apposing cell surfaces. Since oligomerization does not occur in the absence of cell-cell contact, there is a necessary coupling between trans and lateral cis interactions. The molecular mechanism that underlies this coupling will be discussed and is characterized in detail through a combination of fundamental theory and simulations carried out at different levels of granularity.  As essential component in the analysis is a theoretical relationship that is established between 3D binding affinities as measured in solution and 2D affinities between molecules that are constrained to the cell surface.  In addition to the insights that will be discussed in the context of cadherin function, general physical principles that may underlie other cell-cell adhesion processes will be proposed.