Researchers at the Max Planck Institute for Biophysical Chemistry and the German Center for Neurodegenerative Diseases in Göttingen – in collaboration with Polish colleagues – have now “filmed” how a protein gradually unfolds for the first time.
By combining low temperatures and NMR spectroscopy, the scientists visualized seven intermediate forms of the CylR2 protein while cooling it down from 25°C to - 16°C. Their results show that the most instable intermediate form plays a key role in protein folding. The scientists’ findings may contribute to a better understanding of how proteins adopt their structure and misfold during illness. (Nature Chemical Biology, 10. February 2013)
Whether Alzheimer’s, Parkinson’s or Huntington’s Chorea – all three diseases have one thing in common: They are caused by misfolded proteins that form insoluble clumps in the brains of affected patients and, finally, destroy their nerve cells. One of the most important questions in the biological sciences and medicine is thus: How do proteins – the tools of living cells – achieve or lose their three-dimensional structure. Because only if their amino acid chains are correctly folded, can proteins perform their tasks properly.
But what exactly happens when proteins fold or unfold was previously nearly impossible to investigate. With heat and pressure, proteins easily lose their shape – and thus their function. However, such methods are not suitable for directly observing their unfolding process. The intermediate forms that occur in the course of protein folding are much too transient.
With a novel approach, researchers have now succeeded in “filming” the complex process of protein folding for the first time. Scientists at the Max Planck Institute for Biophysical Chemistry (MPIbpc) and the German Center for Neurodegenerative Diseases (DZNE) in Göttingen, together with their colleagues at the Polish Academy of Sciences in Warsaw and at the University of Warsaw, have rendered visible – at atomic resolution – how a protein progressively “loses its shape”.
In doing so, the researchers had pinned their hopes on low temperatures. “If a protein is slowly cooled down, its intermediate forms accumulate in larger quantities than in commonly used denaturation methods, such as heat, pressure, or urea. We hoped that these quantities would be sufficient to examine the intermediate forms with nuclear magnetic resonance (NMR) spectroscopy,” said Markus Zweckstetter, head of the research groups “Protein Structure Determination using MNR” at the MPIbpc and “Structural Biology in Dementia” at the DZNE in Göttingen.
How a protein loses its shape
As research object, Zweckstetter’s team chose a key protein for toxin production in Enterococcus faecalis, a pathogen frequently encountered in hospitals where it particularly jeopardizes patients with a weak immune system. But that is not the only reason why the so-called CylR2 protein is interesting. Some time ago, researchers working with Stefan Becker at the MPIbpc succeeded in elucidating its structure, which shows: Its three-dimensional shape makes CylR2 a particular promising candidate for the scientists’ approach. “ClyR2 is a relatively small protein composed of two identical subunits. This gave us a great chance to be able to visualize the individual stages of its unfolding process in the test tube," explained the chemists Mariusz and Lukasz Jaremko.
Stefan Becker's group undertook the first step: to prepare a sufficient quantity of the protein in the laboratory. Subsequently, the two chemists cooled the protein successively from 25°C to -16°C and examined its intermediate forms with NMR spectroscopy. They achieved what they had hoped for: Their “film clip” shows at atomic resolution how the protein gradually unfolds. The structural biologist Markus Zweckstetter describes exactly what happens in this process: “We clearly see how the CylR2 protein ultimately splits into its two subunits. The individual subunit is initially relatively stable. With further cooling, the protein continues to unfold and at -16 °C it is extremely instable and dynamic. This instable protein form provides the seed for folding and can also be the “trigger” for misfolding.” The scientist’s findings may help to gain deeper insights into how proteins assume their spatial structure and why intermediate forms of certain proteins misfold in the event of illness. (cr)
Mariusz Jaremko, Lukasz Jaremko, Hai-Young Kim, Min-Kyu Cho, Charles D. Schwieters, Karin Giller, Stefan Becker, Markus Zweckstetter
Cold-denaturation of a protein dimer monitored at atomic resolution.
Nature Chemical Biology, DOI:10.1038/NChemBio.1181 (2013)
Prof. Dr. Markus Zweckstetter
Protein Structure Determination using NMR
Phone:+49 551 201-2220
Dr. Carmen Rotte
Press Officer, Public Relations Office
Phone:+49 551 201-1304Fax:+49 551 201-1151
Dr. Dirk Förger
Head of Press and Public Relations, German Center for Neurodegenerative Diseases Bonn
Phone:+49 228 43302-260
Dr. Dirk Förger | Source: Max-Planck-Institute
Further Reports about: Alzheimer > atomic resolution > Chemical Biology > chemical engineering > CylR2 > DZNE > German language > Max Planck Institute > MPIbpc > MR spectroscopy > Nature Chemical Biology > nerve cell > neurodegenerative diseases > NMR spectroscopy > Protein > protein folding > protein structures > synthetic biology
More articles from Life Sciences:
New genetic research finds shark, human proteins stunningly similar
06.12.2013 | Cornell University
Prostate cancer biomarker may predict patient outcomes
06.12.2013 | Vanderbilt University Medical Center
International team of scientists develops new feedback method for optimizing the laser pulse shapes used in the control of chemical reactions
In many ways, traditional chemical synthesis is similar to cooking. To alter the final product, you can change the ingredients or their ratio, change the method of mixing ingredients, or change the temperature or pressure of the environment of the ingredients.
Like an accomplished chef, chemists have become very skilled ...
A genetic defect protects mice from infection with influenza viruses
A new study published in the scientific journal PLOS Pathogens points out that mice lacking a protein called Tmprss2 are no longer affected by certain flu viruses.
The discovery was made by researchers from the Helmholtz Centre for Infection Research (HZI) in Braunschweig in collaboration with colleagues from Göttingen and ...
The Light: Global study gets underway with online user survey
Light has a fundamental impact on our sense of well-being and performance. In cooperation with Zumtobel, a supplier of lighting solutions, Fraunhofer IAO has launched a global user survey of lighting quality in offices. The objective is to identify the best lighting conditions for a variety of spaces and lighting ...
Quantum entanglement, a perplexing phenomenon of quantum mechanics that Albert Einstein once referred to as “spooky action at a distance,” could be even spookier than Einstein perceived.
Physicists at the University of Washington and Stony Brook University in New York believe the phenomenon might be intrinsically linked with wormholes, hypothetical features of space-time that in popular science fiction can provide a much-faster-than-light shortcut from one part of the universe to another.
But here’s the catch: One couldn’t actually ...
A star is formed when a large cloud of gas and dust condenses and eventually becomes so dense that it collapses into a ball of gas, where the pressure heats the matter, creating a glowing gas ball – a star is born.
New research from the Niels Bohr Institute, among others, shows that a young, newly formed star in the Milky Way had such an explosive growth, that it was initially about 100 times brighter than it is now. The results are published in the scientific journal, Astrophysical Journal Letters.
The young ...
06.12.2013 | Materials Sciences
06.12.2013 | Life Sciences
06.12.2013 | Life Sciences
05.12.2013 | Event News
04.12.2013 | Event News
12.11.2013 | Event News