NSF Postdoctoral Fellowship in Biology FY 2021: Uncovering the Molecular Mechanisms of Mitochondrial Proteostasis

这一行动资助了2020财年NSF生物学博士后研究奖学金，扩大了生物学领域代表性不足群体的参与。该研究金支持一项针对该研究员的研究和培训计划，该计划将增加生物学中代表性不足的群体的参与。丽莎·埃顺-威尔逊的这项研究和培训计划的标题是“揭开内膜线粒体蛋白平衡的分子机制”。该奖学金的主办机构是斯克里普斯研究所，赞助科学家是加布里埃尔·兰德博士。蛋白质平衡是细胞控制体内蛋白质的方式，对细胞的生存和生命至关重要。线粒体是细胞的特殊部分，负责创造细胞能量，需要专门的机械来帮助它们进行蛋白质平衡。这种机制的一部分是一种名为YME1L的蛋白质，这种蛋白质在多种动物中都是线粒体发挥作用所必需的。这项提议将决定YME1L如何在线粒体中发挥其功能。为了扩大参与，这位研究员将在斯克里普斯创建一个名为InclusiveScripps的项目，该项目将为未被充分代表的博士后科学家提供指导和支持。人类YME1L蛋白酶的纯化重组版本将接受冷冻电子显微镜观察，以捕捉并可视化其原始状态。为了表征支配YME1L决策过程的机制细节，将在各种背景下研究该复合体，包括ATP结合的活动状态和目标参与的活动状态，以及ADP饱和的休息状态。使用这种显微镜技术，冷冻蛋白质样品的2D电子散射图像可以数学转换为3D模型，从而产生高分辨率的分子细节。鉴于能量驱动的发动机YME1L包含在所有生命和病毒王国中都保守的机械部件，这项研究发现的分子细节将在许多领域产生深远影响。拟议的研究将为PI提供结构生物学(冷冻电子显微镜和断层摄影术)、生物化学(膜纯化技术；功能分析开发)和生物物理学(显微镜光学；统计力学)方面的培训和发展机会。这项工作将提供一个平台，通过指导和培训机会，让像她这样在科学界代表性不足的科学家参与进来。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。

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2020, Broadening Participation of Groups Under-represented in Biology. The Fellowship supports a research and training plan for the Fellow that will increase the participation of groups underrepresented in biology. The title of the research and training plan for this fellowship to Lisa Eshun-Wilson is “Uncovering the molecular mechanisms of inner membrane mitochondrial proteostasis.” The host institution for the fellowship is the Scripps Research Institute and the sponsoring scientist is Dr. Gabriel Lander. Proteostasis, which is how the cell controls proteins within it, is essential for cell survival and life. Mitochondria, which are specialized parts of the cell that are responsible for the creation of cellular energy, require specialized machinery to help them with proteostasis. One part of this machinery is a protein called YME1L, which is required in multiple animals for the mitochondria to function. This proposal will determine how YME1L performs its functions in the mitochondria. To broaden participation, the Fellow will create a program called InclusiveScripps, a program at Scripps that will provide mentoring and support to underrepresented postdoctoral scientists.Purified recombinant versions of the human YME1L protease will be subjected to cryo-electron microscopy to capture and visualize it preserved in its native state. To characterize the mechanistic details that govern the decision-making process of YME1L, the complex will be studied in a variety of contexts, including the ATP-bound and target-engaged active states, as well as ADP-saturated resting states. Using this microscopy technique, 2D electron scattering images of frozen protein samples can mathematically be translated into 3D models yielding high-resolution molecular details. Given that the energy-driven motor YME1L contains mechanistic components that are conserved throughout all kingdoms of life and viruses, the molecular details uncovered by this study will have far-reaching implications across many fields. The proposed research will provide the PI with training and development opportunities in structural biology (cryo-electron microscopy and tomography), biochemistry (membrane purification techniques; functional assay development) and biophysics (microscope optics; statistical mechanics). This work will provide a platform to engage scientists like her who are under-represented in the sciences through mentoring and training opportunities.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.