Watching the Molecular Dance of an ALS Protein

U of T researchers have looked into the biophysics of ALS, the incurable disease that paralyzes and then suffocates its victims.  Professor Lewis Kay was able to watch how a  key enzyme implicated in the disease is able to change its shape with time, providing insight into what may go wrong, leading to the development of ALS.

The enzyme SOD1 is important for detoxifying harmful chemicals generated by the cell as part of its normal activity. About 20 percent of ALS sufferers who have an inherited form of the disease have mutations in this crucial enzyme. The mutation has always puzzled researchers because the enzyme itself is normally strong and stable. It’s made up of two copies of a single protein, and when the protein is fully mature, it gives the enzyme its stability. However, immature copies of the protein are weaker, and often fold into the wrong shape, clumping together in ways that could lead to ALS.

Scientists have known little about how these immature proteins misfold because they lacked the tools to watch the process. But Kay, a biophysicist, has spent his career merging time and space to study how individual biomolecules  are able to change their shapes — and thus their functions.

“We’ve had powerful cameras for many years, but they capture a snapshot,” says Kay, a Professor in the departments of Biochemistry, Molecular Genetics and Chemistry. “Until recently, there hasn’t been the technology to determine the many different conformations that these very important players in the cell can assume —sort of their molecular dance if you like. Molecules change their shapes in reaction to the environment. How do we capture that change? It may be very transient and may involve a very small fraction of the molecules, but it could be very important.”

He and his team used nuclear magnetic resonance spectroscopy to study how immature proteins in the SOD1 enzyme change their shapes in their efforts to grow up. What he saw could possibly be the very molecular beginnings of a form of ALS.

The baby proteins shifted from their default forms into four different shapes. Two of those shapes were similar to the same forms as the adult protein, which are too stable to cause disease. But the other two forms showed protein molecules interacting in strange ways. The shapes may resemble the same misfolded SOD1 proteins that are implicated in ALS.

Next, Kay and his team of biophysicists created 3D models of the proteins. The models allowed them to pinpoint regions of the protein where the bizarre behavior was happening. One day, Kay hopes scientists can target these areas with drugs to stop the formation of toxic versions of SOD1   and block the chain of events that leads to ALS.

“From those different structures we could postulate how even longer and bigger structures could form” says Kay. “We now have models and this is the first step in the rational design of therapies.”

The results of Kay’s research were published online in the journal eLife on June 23, 2015.