Resolve how cell adhesion proteins sense and regulate mechanical cues

Project

My group has played a leading role in determining the biophysical mechanisms by which E-cadherin, an essential cell-cell adhesion protein, tunes adhesion in response to mechanical force. Using single molecule force measurements, we showed for the first time, that E-cadherins form three types of adhesive interactions: catch bonds which, counter-intuitively, become longer lived and lock in the presence of tensile force, slip bonds which become shorter lived when pulled and ideal bonds that are insensitive to mechanical stress (Nature Communications 2014; PNAS 2012; Methods Enzymol. 2017; Phys. Chem. Chem. Phys 2014; J Invest. Dermatol. 2013). We also showed that E-cadherins tune adhesion by changing their binding conformation, thereby switching between these bond types (PNAS 2016). In a related project, we used cell based assembly assays and single molecule binding assays to assign unique roles to different cadherins in adhesion and assembly of desmosomes (J. Cell Sci. 2014). Finally, using single molecule Fluorescence Resonance Energy Transfer (FRET) and AFM force measurements, I also resolved the mechanism by which E-cadherins mediate cell adhesion (Structure 2009, PNAS 2009). We showed that cadherins first transiently interact with each other and then undergo a structural change that strengthens adhesion.