Interview
Pernilla studies protein folding, assembly, structure and stability
Name: Pernilla Wittung Stafshede
Diseases such as Alzheimer\'s, Parkinson\'s, Skellefteå Disease (Familial amyloidosis), as well as certain forms of cancer develop because proteins in the cells begin to fold incorrectly (misfolding), or because they begin bind to other protein chains or metallic ions. Pernilla Wittung Stafshede focuses her research on these processes.
“It\'s very fascinating to try to simultaneously understand how proteins reach their active forms and what can go wrong during this process, which is incredibly difficult,” she notes.
Proteins are long chains of amino acids that are linked in a specific order based on our genetic code. In order to be activated, each chain needs to be folded into a specific structure in the cells.
“The question is how the chains fold. Nature knows how it happens, as protein folding occurs all the time in living organisms. If the chains would randomly test the various forms it would take an infinite time, instead there must be something that sets them in the right direction,” says Pernilla.
Pernilla, who is a professor of biological chemistry, has made many fundamental discoveries about how proteins that bind metals (metal proteins) or proteins that bind to other protein chains (oligomers) are linked to folding and binding. Many of the key proteins in the cell must bind to metals or other protein chains in order to perform properly. In addition, free metals are toxic and inactive protein-protein interactions can lead to diseases.
“It appears that metals can bind to the chain prior to the folding and accelerate the formation of the active protein. We have seen a case in which the process is 1000 times faster if a copper ion binds to the protein before it folds itself, compared to the contrary.
For several years, she has been studying the significance of cellular environment on protein folding properties, form and function.
“Protein folding has been mostly studied in aqueous solution. But the cells are filled with other proteins, DNA, ribosomes, etc; up to 40 percent of cell volume may be occupied by other molecules. This reduction in accessible volume can affect proteins in many different ways, but nobody has previously tested this and has conducted biophysical experiments in environments that mimic the cell.
Pernilla and her colleagues recently made an unexpected discovery.
“We found out that the folded protein became more stable and it also folded more rapidly in true-to-nature cellular environments. This is consistent with theoretical predictions. Nobody could guess where we found that the protein\'s form could also be modified in the cell environment other than in aqueous solution.”
The protein\'s form plays a critical role for its function.
“We experimented with a model protein from the Lyme disease (borrelia) bacterium. In the normal folded form of the protein present in diluted water solutions a major antigen cannot be seen, but when the protein was placed in cell-like environment it collapsed into a sphere and then the antigen popped out and was visible. This may explain why so many antibodies are produced to this antigen in infections, an issue which has previously been unclear.
How to understand the biophysical behaviour of proteins involved in human cellular copper transport is another important research area for Pernilla Wittung Stafshede.
“There isn’t any free copper in cells, they are dangerous, but instead there are dedicated proteins that transport the metal to needy proteins. Nobody yet understands how this is implemented on a mechanical level, what the driving force is and how the temporary protein-copper complex appears.”
Since copper ions can play a major role in ALS, Alzheimer\'s and Parkinson\'s disease, it is an important mystery to solve. Copper has also been found in many cancer tumours.
“If we understand how copper is transported normally in the cell, we can perhaps come up with ways to prevent diseases that are affected by the development of copper,” says Pernilla Wittung Stafshede.
More about Pernilla:
Personal interests: playgrounds (nowadays), trips to exciting places in the world (before we had children)
Hidden talent: plays the accordion
Likes to eat: Marabou chocolate
Born: 1968
