Siavash Vahidi

Email Address
[email protected]
Research Description

In my lab we look at biomolecular machines, this is, large molecules that perform key functions in the cells of living organisms. We are interested in how these biomolecular machines operate in both healthy and diseased states. In particular, we study the molecular machinery of Mycobacterium tuberculosis, the species of bacteria that causes tuberculosis.

Research Summary

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 proteasome 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:
1) 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?
2) How are substrates selected for tagging and degradation?
3) What is the molecular basis of antibiotics that operate by disrupting proteasomal protein degradation?

Techniques Used

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)

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