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

该行动为2020财年美国国家科学基金会生物学博士后研究奖学金提供资金，扩大生物学中代表性不足群体的参与。该奖学金支持研究员的研究和培训计划，该计划将增加在生物学中代表性不足的群体的参与。Lisa esun - wilson的研究和培训计划的标题是“揭示细胞膜线粒体蛋白酶抑制的分子机制”。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其内部蛋白质的方式，对细胞的生存和生命至关重要。线粒体是细胞中专门负责产生细胞能量的部分，需要专门的机器来帮助它们进行蛋白质平衡。这个机制的一部分是一种叫做YME1L的蛋白质，它是多种动物线粒体运作所必需的。这一提议将确定YME1L如何在线粒体中发挥其功能。为了扩大参与范围，该研究员将在斯克里普斯创建一个名为inclesvescripps的项目，该项目将为代表性不足的博士后科学家提供指导和支持。纯化的重组人YME1L蛋白酶将在低温电子显微镜下捕获并观察其在天然状态下的保存情况。为了描述控制YME1L决策过程的机制细节，将在各种情况下研究该复合物，包括atp结合和靶标参与的活性状态，以及adp饱和的静息状态。利用这种显微镜技术，冷冻蛋白质样品的二维电子散射图像可以在数学上转化为三维模型，从而产生高分辨率的分子细节。鉴于能量驱动的马达YME1L包含在所有生命王国和病毒中保守的机械成分，这项研究揭示的分子细节将在许多领域产生深远的影响。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扫描），生物化学（膜净化技术；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。这项工作将通过指导和培训机会，为像她这样在科学领域代表性不足的科学家提供一个平台。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。

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.