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

细胞对机械力的感知和转换影响生物学中的基本过程，如细胞粘附，胚胎发育，组织修复。机械力的转换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消除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体中充当相邻细胞之间的机械传感枢纽。 由于AJ复合物是高度灵活的，确定它们的结构和动力学构成了分子生物物理学的挑战。 本项目旨在通过一种新的整合结构生物学方法来阐明AJ核心复合物的机械传感机制。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，这项研究有助于下一代世界级中子散射国家基础设施的发展，以及社区外展计划，以扩大STEM教育和研究的参与。 具体而言，该项目将采用尖端静态和动态中子散射，理论物理和分子模拟，以确定AJ的机械敏感核心复合物的结构和动力学。 借助于选择性氘化，中子散射，特别是中子自旋回波光谱，可以探测纳米长度尺度和纳秒到微秒时间尺度上的大分子复合物的动力学，这填补了细胞生物物理学/单分子光谱学和高分辨率结构生物学之间很大程度上未探索的时空利基。 该奖项反映了NSF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.