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Protein Knots: Key to Parkinson’s Disease and Obesity?
March 27, 2014   
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Mysterious knots on human proteins may have an impact on the development of Parkinson’s disease and obesity. A Polish scientist has set out to find out how these knots are formed.

Biologists learned about the existence of these strange knots 10 years ago; knotted proteins remain one of their biggest research challenges to this day. Joanna Sułkowska, Ph.D., from the University of Warsaw Faculty of Chemistry, is trying to solve the puzzle of knotted proteins, working together with researchers from the University of California at San Diego, the Scripps Research Institute in La Jolla, California, and Rice University in Houston, Texas. She intends to design and carry out an experiment that will make it possible to discover how the knotting process unfolds and how to make such knots disappear. Sułkowska has received zl.100,000 from the Foundation for Polish Science for the experiment.

Scientists cannot apply the simplest solution and cut the knot, because then the protein would lose its biological functions. They must therefore look for a more subtle method. As part of the experiment, they plan to attach special diodes to the tips of a protein in order to track its movement and see how a knot forms. At the same time, they will conduct simulations on a computer.

So far no one has managed to carry out an experiment showing just how a knot is formed in a real protein, as opposed to one generated in a computer simulation. Neither has there been an experiment that would allow researchers to untie a protein knot. The so-called FRET experiment planned by Sułkowska and her colleagues aims to enable scientists to understand the functions of specific knots. It may prove that these knots have an impact on people’s health.

“We now know that knotted structures exist in several hundred proteins. Among these are those responsible for Parkinson's disease. We expect that [protein knots] may contribute to the development of this disease, but we do not know exactly how," says Sułkowska.

It is also known that a knotted structure is created by a protein called leptin, which can lead to obesity. Depending on the form in which it occurs, it either inhibits or stimulates the sending of information to the brain about whether we are full or hungry. Sułkowska’s work may thus help understand the causes of obesity, Parkinson’s disease, but also HIV and leukemia.

In the case of proteins, only four fairly simple types of knots are known. Sułkowska has discovered the most complicated of these. Her team’s research has demonstrated that this complex knot consists of several smaller knots connected with loops. They have also managed to perform simulations that show how the smallest knotted protein could develop.

However, despite research successes, when looking at a protein under a microscope, the scientists cannot yet tell if it is knotted. It resembles a ball in which it is difficult to see anything. Only computer simulations make it possible to see exactly what a specific protein looks like and where knots are formed.

To conduct further research on proteins, Sułkowska has received a 150,000-euro Installation Grant from the European Molecular Biology Organization (EMBO).

Installation Grants are intended for researchers returning to Poland or already working in this country after spending time abroad, and planning to set up their own laboratory. The grant is for three years, extendible by a further two years. Sułkowska’s team will be composed of physicists, bio-information scientists, molecular biologists and mathematicians.

Olga Majewska
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