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

细胞对机械力的感知和传导影响着细胞粘附、胚胎发育、组织修复等生物学的基本过程。传导机械力对于触觉和听觉等感官也是必不可少的。然而，细胞蛋白质机器感知和转导机械力的分子机制仍有待阐明。细胞-细胞粘附连接（AJ）大分子复合物在多细胞生物中充当相邻细胞之间的机械传感中心。由于AJ配合物具有高度的柔韧性，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颖的综合结构生物学方法阐明AJ核心复合物的机械传感机制。鉴于其跨学科性质，合作研究为研究生和本科生提供了多学科培训的机会。此外，本研究有助于发展下一代世界一流的国家中子散射基础设施，并有助于社区外展计划，以扩大STEM教育和研究的参与。具体来说，该项目将采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物的结构和动力学。在选择性氘化的帮助下，中子散射，特别是中子自旋回波光谱，可以在纳米长度尺度和纳秒到微秒时间尺度上探测大分子复合物的动力学，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尚未开发的时空空缺。这种独特的综合方法将为AJ大分子机械传感的机制提供新的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.