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

细胞对机械力的感知和传递影响着细胞黏附、胚胎发育、组织修复等生物学中的基本过程。机械力的传递对触觉和听觉等感官也是必不可少的。然而，细胞蛋白质机械感知和传递机械力的分子机制仍有待阐明。在多细胞生物体中，细胞-细胞黏附连接(AJ)大分子复合体作为相邻细胞间的机械传感枢纽。由于AJ络合物具有高度的柔性，确定其结构和动力学对分子生物物理学提出了挑战。本项目旨在通过一种新的综合结构生物学方法来阐明AJ核心复合体的机械传感机制。鉴于其跨学科的性质，合作研究为研究生和本科生提供了多学科的培训机会。此外，这项研究还有助于发展下一代世界级的中子散射国家基础设施，并有助于社区推广计划，以扩大对STEM教育和研究的参与。具体地说，该项目将利用尖端的静态和动态中子散射、理论物理和分子模拟来确定AJ的机械敏感核心复合体的结构和动力学。中子散射，特别是中子自旋回波谱，可以在纳米尺度和纳秒到微秒的时间尺度上探测大分子复合体的动力学，填补了细胞生物物理/单分子光谱和高分辨率结构生物学之间一个很大程度上未被探索的时空空白。这种独特的集成方法将为AJ大分子机械传感的基础机制提供新的见解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.