Cells in tissue exert forces as they squeeze, stretch, flex and pull on each other. These forces are incredibly small, on the scale of piconewtons, but they are essential for cell survival and growth. Key proteins involved in sensing mechanical forces, are the cadherin family of cell-cell adhesion proteins. Cadherins mechanically couple neighboring cells, transmit extracellular forces to the cytosol and transduce mechanical forces into biochemical signals. However, the biophysical mechanisms by which cadherins sense and interpret mechanical forces and regulate adhesion are unknown. To target this critical gap, we study how cadherins sense and respond to mechanical signals. We also develop new bioengineering tools that can be used to study cadherins with previously unprecedented resolution. Our research is targeted around the following projects:
- Resolve how classical cadherin cell adhesion proteins sense and regulate mechanical cues: We have played a leading role in determining the biophysical mechanisms by which classical cadherins tune adhesion in response to mechanical force. We showed, for the first time, that cadherins adopt different conformations with distinctly different adhesive properties and tune adhesion by switching between these conformations . Recently, we also directly resolved, for the first time and at the single molecule level, the regulation of cadherin extracellular conformation and adhesion by cytoplasmic proteins (inside-out regulation of adhesion).
- Determine biophysical determinants for the assembly and adhesion of desmosomes: Desmosomes are essential adhesive organelles present in tissue like the heart and skin, which are exposed to mechanical stress. However, the biophysical mechanisms that govern the assembly and strength of desmosomes are unknown. Desmosomes are composed of two types of adhesive proteins and we have successfully assigned unique roles to each of these proteins in adhesion. We have also identified the molecular steps involved in desmosome assembly. Finally, we recently developed a molecular technology to discover novel transmembrane protein interactions in cells and used this technology to map proteins that interact with the desmosome.
- Develop microscope for ultrasensitive-measurement of single-molecule interaction and conformation: We are developing the world’s first fully-automated, microscope that can simultaneously measure interaction forces between single adhesive proteins and their corresponding force-induced conformational changes. We anticipate that this instrument will enable mechanical processes in biology to be investigated in previously unparalleled ways by enabling a user to directly apply force on a single molecule while simultaneously imaging the resulting change in structure or function.