September 19-23 is National Postdoc Appreciation Week. Since 2009, the National Postdoctoral Association (NPA) has sponsored this annual celebration to recognize the significant contributions that postdoctoral scholars make to research and scientific discovery. Check out the NPA website to view the virtual and in-person events being held this week.
This week, BPS will be highlighting postdoc members on the blog. Today, read about Meghna Gupta, University of California San Francisco.
What is your current position?
Postdoctoral researcher (Title: Specialist)
Please share a brief description of your research.
Cell membrane demarcates the distinction between living cells and surroundings. It controls the movement of entities like nutrients, toxins, metabolites, and signal transduction etc. across and sustains life. I got trained in protein biochemistry, functional analysis of proteins and cell biology in my master’s as well as Ph.D. in India. I am amalgamating my previous experience and membrane protein structural biology training in my postdoctoral training to figure out mechanism behind vital processes.
One of such processes, I am deeply interested in, is ‘peroxisomal function and its disease relevance’. I started with exploring ATP-binding cassette (ABC) transporters of ‘D subfamily’ (ABCD1, ABCD2 and ABCD3) which are present on peroxisomal membranes and transport fatty acids to the peroxisome lumen. Fatty acids undergo ⍺- and β-oxidation in the peroxisome and fuel cells by making the shorter fatty acids suitable for mitochondria to generate ATP. I determined high-resolution structures of ABCD3 protein using cryogenic-electron microscopy (cryoEM) in inward-open conformations which will be published soon. We also discovered new organelle tethers between ER and peroxisomes mediated by ATF6⍺ and ABCD3 respectively in collaboration with Walter lab and Weissman labs at UCSF. We aim to study this unique connection of a fatty-acid transporter to unfolded protein response by visualizing it through cryoEM.
In relation to an auto-immune disease- Neuromyelitis Optica (NMO), I initiated a cryoEM-based project for determination of the human water channel AQP4 in conjunction with patient-derived antibodies. I obtained high-resolution structures of AQP4-antibody complexes. These are the first structures where interface of the autoantibody and AQP4 could be observed. We are doing virtual drug screening and testing in vitro which compounds can efficiently inhibit the antibody binding. These autoantibodies recognize different patterns of AQP4 extra-cellular loops. It is shaping up to be molecular basis for drug discovery for NMO to alleviate the disease.
Stroud lab has given me a valuable opportunity to be able to work on various membrane proteins. Along with these main projects, I have contributed to many projects during my stay in the lab as reflected in my publications.
As COVID19 caused adjustments, from February 2020-present, I volunteered to work in UCSF’s Covid-19 research initiative- QCRG-SBC (QBI Coronavirus Research Group Structural Biology Consortium). I am a team leader for the consortium and has been part of high impact publications to combat Covid-19. We are attempting to understand the human-viral protein interactions to determine the cellular mechanisms that Covid-19 infection impacts.
What are some potential applications of your research?
The SARS-CoV-2 research, I am part of, in the last 2 years has already added fundamental knowledge of host‑viral protein interactions. One of the structures we solved of human mitochondrial TOMM70 and SARS-CoV-2 Orf9b caught a lot of attention and was featured in NIH director’s blog- ‘Protein Mapping Study Reveals Valuable Clues for COVID-19 Drug Development’ (https://directorsblog.nih.gov/2020/10/27/protein-mapping-study-reveals-valuable-clues-for-covid-19-drug-development/). We are continuing to structurally define SARS-CoV-2 proteins and unraveling their functions. Our structure of the non-structural protein 2 (Nsp2) is available as a preprint (https://www.biorxiv.org/content/10.1101/2021.05.10.443524v1) was cited by the groundbreaking Alphafold publication in Nature (https://www.nature.com/articles/s41586-021-03819-2) as we demonstrated the how Alphafold can complement CryoEM and assist in structure determination in addition to structure prediction. We are expanding the knowledge we gained from the SARS-CoV-2 to the other RNA viruses that have the potential to cause future pandemics.
I determined the structures of NMO patient-derived antibodies with their target aquaporin (AQP4) provide a high-resolution interface for drug-development and molecular aspects of how these auto-immune disease antibodies bind to AQP4 and manifest as disease.
In the ‘peroxisome biology’ project, I am discovering new aspects of peroxisomal membrane protein and their relevance in diseases.
How might your research be relevant to those who are not working in your specific field?
My research has a very broad impact and our ongoing collaborations with scientists around the world, I think, is a testimony to this. The projects I have worked on as well as the ongoing ones have opened new avenues of research that has impact on and can be easily incorporated into research in other fields.
What is your favorite thing about biophysics?
I consider biophysics as a true integration of several areas of sciences to understand biological processes.
What do you like to do outside of work?
Exploring cities on foot, Hiking
Do you have a website where our readers can view your recent research and follow your career? Or want to share professional social media handles?
https://profiles.ucsf.edu/meghna.gupta
https://scholar.google.com/citations?user=XZXo6-EAAAAJ&hl=en
https://twitter.com/MeghnaG27