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

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.