Collaborative Research: Nanoscale structure and dynamics of a cell-cell adhesion complex

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The sensing and transducing of mechanical forces by cells influence fundamental processes in biology like cell adhesion, embryo development, tissue repair. Transducing mechanical forces is also essential for senses like touch and hearing. However, the molecular mechanisms by which the cellular protein machineries operate to sense and transduce mechanical forces remain to be elucidated. The cell-cell adhesion adherens junction (AJ) macromolecular complexes serve as mechanosensing hubs between neighboring cells in multicellular organisms. Because the AJ complexes are highly flexible, determining their structure and dynamics poses a challenge to molecular biophysics. This project aims to elucidate the mechanosensing mechanism of the AJ core complex by a novel integrative structural biology approach. Given its interdisciplinary nature, the collaborative research provides multidisciplinary training opportunities for graduate and undergraduate students. Moreover, this research contributes to the development of next generation world class national infrastructure for neutron scattering, and to the community outreach programs to broaden participations in STEM education and research. Specifically, this project will employ cutting edge static and dynamic neutron scattering, theoretical physics and molecular simulation to determine the structure and dynamics of the mechanosensitive core complex of the AJ. With the aid of selective deuteration, neutron scattering, particularly neutron spin echo spectroscopy, can probe the dynamics of macromolecular complexes on nanometer length scales and on nanosecond to microsecond timescales, which fills a largely unexplored spatial-temporal niche between cell biophysics/single molecule spectroscopy and high-resolution structural biology. The uniquely integrated approach will provide new insight into the mechanism underlying AJ macromolecular mechanosensing.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.