Diving into Molecular Mysteries
Ever wonder how a protein takes a chemical signal from the outside of a cell, and uses it to start talking to signaling proteins on the inside of the cell? How about how a protein is spun out of a cell factory called a ribosome, and within milliseconds takes on a single structure out of a possible number of conformations greater than the number of atoms in the universe?
These are the types of preoccupations for Professor Scott Prosser from the Department of Chemical and Physical Sciences at U of T Mississauga, who is in an elite group of Canadian researchers to have received a significant NSERC Discovery Accelerator Supplement (DAS) grant. His research focuses on the mechanisms of complex biological processes such as protein misfolding and diseases of aggregation, motions of enzymes and the relation to function, signaling mechanisms of G-protein-coupled receptor (GPCR) membrane proteins, and molecular imaging of proteins and nanoparticles by magnetic resonance imaging (MRI).
The common thread in all of these projects is a technique called Nuclear Magnetic Resonance (NMR), which makes it possible to identify structures and conformations of macromolecules, thereby gaining insight into their function. “We don’t figure out how enzymes and signaling proteins work by looking at their lowest energy state, handed to us by crystallography,” says Prosser. “Rather, by NMR we are able to examine the entire landscape of structures and begin to figure out how many complex biological processes work.”
For Prosser, who is also the Director of the Master of Biotechnology program, his research garnered further attention when his collaborator, Professor Brian Kobilka, an MD from Stanford University, won the Nobel Prize in Chemistry in 2012.
“Brian is a noted X-ray crystallographer and structural biologist who figured out a way to obtain structures of GPCRs. A third of all pharmaceuticals actually target these proteins for ailments such as depression, insomnia, asthma, and heart disease,” explains Prosser. “We want to understand the influence of GPCR drugs on the energy landscape of GPCRs. We are trying to sort out the key states that are involved in their function and identify how these states are connected, thanks in part to a decade of groundbreaking crystallography which preceded this work.” Prosser and his collaborators are also interested in understanding how drugs alter this energy landscape, and the consequent signaling processes.
The last four years of work have seen shared publications in top-notch journals such Nature, the Journal of Biological Chemistry, Cell, and most recently, the Journal of the American Chemical Society. “The work has been tough but very rewarding. And about the only thing that has changed since Brian received the Nobel Prize was that he became impossible to reach on the phone.” Professor Kobilka will be visiting U of T as a keynote speaker for the Neuroscience Distinguished Lectureship Series being held at U of T’s St. George campus June 10-11 as part of the Collaborative Program in Neuroscience (CPIN) Research Day activities.
With the supplemental NSERC funding he received, Prosser plans to promote his diverse research projects in protein folding and misfolding, which has ramifications for many amyloidosis afflictions, such as Alzheimer’s, and also for prion diseases like Creutzfeld-Jakob disease, a degenerative neurological disorder that is currently incurable and fatal. With amyloid disease, proteins adopt states that lend themselves to aggregation, with disastrous consequences to the cell. By honing in on radio frequency signals from fluorine atoms in the protein, Prosser obtains a molecular fingerprint of the amyloid protein in a given state. This kind of information allows us to piece together a mechanism, suggesting how proteins aggregate, adopt amyloid states and initiate disease.
When students ask him about the role of research in universities, Prosser likes to defend good, old-fashioned basic research, and he is grateful to NSERC for allowing this endeavour. “While patents and commercialization are worthy pursuits, university researchers have the opportunity to truly discover, challenge old paradigms, and elevate humanity,” says Prosser. He feels that university research should be risky.
The NSERC DAS Program aligns with this notion quite precisely in providing additional resources to researchers exploring novel and revolutionary concepts that have the potential for groundbreaking advances. In 2013, NSERC awarded $15 million to 125 applications in the DAS competition. These supplements are valued at $120,000 over three years and are intended to advance and maximize the impact of exceptional research programs.