Navigation Links
Protein 'filmed' while unfolding at atomic resolution

By combining low temperatures and NMR spectroscopy, the scientists visualized seven intermediate forms of the CylR2 protein while cooling it down from 25C to -16C. 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.

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 Gttingen, 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 Gttingen.

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 infects 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 25C to -16C 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)

Contact: Dr. Dirk Frger
Helmholtz Association of German Research Centres

Related biology news :

1. Key protein revealed as trigger for stem cell development
2. Compound stimulates tumor-fighting protein in cancer therapy
3. FASEB SRC announces conference registration open for: Arf and Rab Family G Proteins
4. FASEB SRC announces: Molecular Mechanisms & Physiological Consequences of Protein Aggregation
5. FASEB SRC announces conference: Matricellular Proteins in Development, Health, and Disease
6. Protein origami: Quick folders are the best
7. Pitt team finds Achilles Heel of key HIV replication protein
8. First special edition updating progress on efforts to map human proteins
9. Study: Odd biochemistry yields lethal bacterial protein
10. Protein structure: Immune system foiled by a hairpin
11. How the protein transport machinery in the chloroplasts of higher plants developed
Post Your Comments:
(Date:11/12/2015)... Nov. 12, 2015  A golden retriever that stayed ... dystrophy (DMD) has provided a new lead for treating ... the Broad Institute of MIT and Harvard and the ... . Cell, pinpoints a protective ... the disease,s effects. The Boston Children,s lab of ...
(Date:11/10/2015)... , Nov. 10, 2015  In this ... the basis of product, type, application, disease ... in this report are consumables, services, software. ... are safety biomarkers, efficacy biomarkers, and validation ... report are diagnostics development, drug discovery and ...
(Date:11/4/2015)... ALBANY, New York , November 4, 2015 /PRNewswire/ ... According to a new market report published by Transparency ... Size, Share, Growth, Trends and Forecast 2015 - 2022", ... value of US$ 30.3 bn by 2022. The market ... during the forecast period from 2015 to 2022. Rising ...
Breaking Biology News(10 mins):
(Date:11/25/2015)... SAN DIEGO , Nov. 25, 2015 ... that management will participate in a fireside chat discussion ... New York . The discussion is ... Time. .  A replay will ... Contact:  Media Contact:McDavid Stilwell  , Julie NormartVP, Corporate ...
(Date:11/24/2015)... , Nov. 24, 2015  Asia-Pacific (APAC) ... research organisation (CRO) market. The trend of outsourcing ... lower margins but higher volume share for the ... and scale, however, margins in the CRO industry ... (CRO) Market ( ), finds that ...
(Date:11/24/2015)... SAN DIEGO , Nov. 24, 2015 Halozyme Therapeutics, ... Jaffray Healthcare Conference in New York on ... Dr. Helen Torley , president and CEO, will provide a ... New York at 1:00 p.m. ET/10:00 a.m. ... communication and investor relations, will provide a corporate overview. --> ...
(Date:11/24/2015)... ... 2015 , ... International Society for Pharmaceutical Engineering (ISPE) closed ... events for pharmaceutical manufacturing: 2015 Annual Meeting. The conference took place in Philadelphia, ... number of attendees in more than a decade. , “The 2015 Annual ...
Breaking Biology Technology: