Assistant professor Scott Prosser talks about the projects in his University of Toronto Mississauga chemistry research lab with the ease some people might have when they describe creating their signature dish in the kitchen. But while the latter might discuss the essential ingredients that make their eggplant parmigiana unique, Prosser explains the intricacies that make protein structures and interactions so fascinating.
Growing up in the Maritimes Prosser aspired to become a doctor, but other diversions – namely math and physics – came into play, and he soon revised his career goal to that of scientist. With the various protein-research projects and sub-projects that he currently conducts and supervises, the “marriage of math and physics to biology” is a great match for Prosser, who regularly serves up espresso in his lab as an ice-breaking ritual for him and his graduate students. “It’s a great way to have them sit in one place and talk science with you,” he says. “My group is very passionate about work and science, and they have become avid espresso fans by now.”
But it’s not all work and science for Prosser, who notes on his lab homepage how to get to University of Toronto Mississauga using public transit, or he suggests that “you could also kayak from outside the Biotech building to downtown, though you should reserve about 8 hours for the trip.” While kayaking to campus might seem a tad extreme for most people, for Prosser, who is also a triathlon devotee, the challenge is not so implausible. “I used to compete [in running] as a youth,” Prosser says, “and I adopted triathlons because I like competition and because it’s a lifestyle for me.”
Olympic-distance triathlons are Prosser’s race of choice, and his favourite event is the Wildflower, held annually in early-May in Lake San Antonio, California. “It’s good for Canadians because it gives us a reason to train through the winter,” Prosser says. “And if you don’t train, the 1.5 km swim, 40 km bike ride and 10 km run through the mountains at 100° F will make you wish you ate less cheese.” Although training for and competing in triathlons are of great importance to Prosser, he admits that it takes a backseat to the research that he does in the lab, studying the lives of proteins.
“Proteins are sophisticated macromolecules whose infinite variations in structure and function stem from the way in which building blocks – called amino acids – are strung together,” Prosser explains. “Many proteins are enzymes which catalyze virtually every chemical reaction that takes place in living cells. Subtle changes in the sequence or order of amino acids in a protein may have dire consequences for the structure or function of the protein.” Prosser offers sickle-cell anemia, an inherited disease, as an example: it results from a mutation in the β-globin chain of a protein called hemoglobin, where a single amino acid is replaced with a less polar one at one site in the protein. Even subtle changes in the environment of a protein may precipitate changes in protein conformation leading to disorders such as Mad Cow disease, says Prosser.
Protein physical chemists seek to understand the relationship between protein functions and their structural and dynamical properties. They can interrogate protein structure and dynamics in several ways, although X-ray crystallography and Nuclear Magnetic Resonance (NMR) remain two of the most important techniques. The protein structure-function relationship is important to fundamental research and to the design of drugs and therapeutics which interact, inhibit, or change the behaviour of the protein.
Prosser’s lab focuses on studies of membrane proteins, which make up 20-30% of all proteins. As an example, one research project involves an important class of membrane proteins called G Protein-Coupled Receptors (GPCRs) that cannot be readily studied using conventional techniques. These proteins may be appropriately tagged with fluorine atoms and interrogated by an NMR technique which gives the signal of the fluorine tags.
Once these tags are strategically placed throughout the protein through techniques called mutagenesis and biosynthetic labeling, a procedure is used to measure the approximate distance between the tags. “The distance between the tags is important in order to stitch together a model of the three-dimensional structure,” Prosser explains.
His lab has been using this fluorine-tagging technique for about two years, but it has been an arduous process because of the challenge in synthesizing these fluorinated amino acids, which are enriched with specific nuclei in order to create unique signals for each tagged amino acid. “The other virtue of these labeled amino acid markers is that their signals are acutely sensitive to binding, dynamics, and conformational changes that a protein under study might undergo,” Prosser says. “After all, the interesting aspects of protein biochemistry typically involve change of some kind.”
Another method his lab employs to further understand membrane protein structures involves using oxygen to probe surfaces of membrane proteins in order to better see their shapes. The experiment involves the use of special sample tubes made of sapphire, designed to withstand pressures as high as 300 times atmospheric pressure. “The application of pressurized oxygen creates the right concentration of dissolved oxygen in the protein. The oxygen ‘lights up’ the protein surface, but not uniformly,” Prosser explains. “The part of the membrane protein that sits in the very middle of the membrane is most affected by oxygen. And the part of the membrane protein that is at the water-membrane interface will also have a unique effect from dissolved oxygen, thereby helping to identify the positioning of protein atoms in the membrane.” Prosser says this methodology has enabled a greater sensitivity in their experiments, and he is enthusiastic about where this technique might further lead, particularly in studies of very disordered proteins which are important in signaling, cancer research, and fundamental biochemistry.
It is this range of possibilities for protein study that feeds Prosser’s ‘fascination’ (a word that comes up often when he speaks about proteins). He suggests that because his lab is “interested in protein structure and dynamics, there are billions of things [they] could possibly study.” When discussing his work, it is obvious that the various protein projects with which Prosser is involved allow him to maintain his fervour for his field of research, and consistently offer new challenges to fuel his interest. And, much like the passionate chef who can offer up variations to take a great dish to the next level, Scott Prosser is an inspired scientist, eager to see where these innovative protein studies and research techniques might lead him and his team in the next phase of physical chemistry.