Dr. Siavash Vahidi

As a teenager in high school, my main goal was… to play basketball in the NBA! A combination of a knee injury and inadequate basketball skills made me re-evaluate my life choices. Less time on the basketball court allowed me to focus on school and finish close to the top of my class as an undergrad. My interest in biophysical mass spectrometry lured me to the laboratory of Prof. Lars Konermann at Western for a PhD, where I developed and applied biomolecular mass spectrometry methods to study protein folding, structure, and dynamics. After struggling for the first two years of my doctoral studies, during which I strongly considered quitting, I managed to be productive and won the Paul de Mayo award for the best PhD thesis in the department. My fascination with biomolecular machines set me on a path for a career in academia and to a CIHR postdoctoral fellowship with Prof. Lewis Kay at the University of Toronto and The Hospital for Sick Children. Through my postdoctoral research, I broadened my scientific horizons and learned to use biomolecular nuclear magnetic resonance (NMR) spectroscopy to study the Clp protein degradation machinery. I also worked closely with the Rubinstein group at SickKids to complement our studies with electron cryomicroscopy. My research group at University of Guelph takes advantage of an integrative approach in structural biology by combining various methods, including mass spectrometry and NMR, which can provide a detailed picture of the functions and dysfunctions of mega Dalton-sized biomolecular machines in health and disease.

• Postdoctoral fellowship: Departments of Molecular Genetics and Biochemistry, University of Toronto & Molecular Medicine Program, The Hospital for Sick Children
• PhD: Departments of Chemistry and Biochemistry, University of Western Ontario
• BSc: Department of Chemistry, National University of Iran, Tehran

The Vahidi research group develops and applies state-of-the-art methods to investigate the structure, function, and dynamics of large biomolecular machines in order to solve problems of biological and clinical importance.

A key focus of the group is on the protein degradation machinery that helps to maintain proper level of proteins (protein homeostasis) in Mycobacterium tuberculosis, the causative agent of TB, the world's single largest infectious killer that is annually responsible for 1.5 million deaths. Protein degradation in M. tuberculosis is partly handled by the proteasome machinery where the 20S core particle (the protease) collaborates with the mycobacterial proteasomal activator (Mpa, the unfoldase) to engage and destroy substrates in an ATP-dependant manner. M. tuberculosis relies heavily on robust proteasome function to survive the immune system of the host, rendering this mega-Dalton sized system an attractive drug target in the pharmaceutical industry. Several critical and outstanding questions remain that our group aims to answer:

• What is the assembly mechanism of the M. tuberculosis proteasome core particle and its regulatory particles?
• What is the role of allostery and long-range interactions in the machinery that tags substrates for proteasomal degradation?
• How are substrates selected for tagging and degradation?
• What is the molecular basis of antibiotics that operate by disrupting proteasomal protein degradation?

Most of our work is based on the use of modern biomolecular electrospray mass spectrometry (ESI-MS) (e.g. H/D exchange, covalent labeling, native MS, BioID, etc.) and high-field NMR spectroscopy (e.g. methyl-TROSY). These powerful methods are highly complementary and allow us to tackle challenging problems within our own group. Because of the dominant role that these two methods play in biological and chemical research, trainees from our lab will be well-positioned in the job market after graduation. Researchers in our laboratory will also receive training in a wide range of other biochemical, biophysical, and computational (e.g. python computer programming, Linux, etc.) approaches available at the core facilities of the University of Guelph.

1. M. Turner, A. B. Uday, A. Velyvis, E. Rennella, N. Zeytuni, and S. Vahidi, “Structural basis for allosteric modulation of M. tuberculosis proteasome core particle” Nature Communications 16, 3138 (2025) https://doi.org/10.1038/s41467-025-58430-0

2. M. Goncalves, A. B. Uday, T. J. B. Forrester, S. Q. W. Currie1, A. S. Kim, Y. Feng, Y. Jitkova, A. Velyvis, R. W. Harkness, M. S. Kimber, A. D. Schimmer, N. Zeytuni, and S. Vahidi, “Mechanism of allosteric activation in human mitochondrial ClpP protease“ Proc. Natl. Acad. Sci. U.S.A. 122, e2419881122 (2025) https://doi.org/10.1073/pnas.2419881122

3. A. Plourde, J. C. Ogata-Bean, and S. Vahidi “Mapping the structural heterogeneity of Pup ligase PafA using H/D exchange mass spectrometry” J. Biol. Chem. 301, 108437 (2025) https://doi.org/10.1016/j.jbc.2025.108437

4. B. T. V. Davis, A. Velyvis, and S. Vahidi, “Fluorinated ethylamines as electrospray-compatible neutral pH buffers for native mass spectrometry”, Analytical Chemistry, 95 (48) 17525-17532 (2023) https://pubs.acs.org/doi/abs/10.1021/acs.analchem.3c02640