Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How Human Cells Can Dissolve Damaging Protein Aggregates

11.08.2015

Heidelberg researchers decode fundamental mechanism using in-vitro experiments

Cellular repair systems can dissolve aggregated proteins and now Heidelberg researchers have successfully decoded the fundamental mechanism that is key to dissolving these protein aggregates in human cells.

Their in-vitro experiments uncovered a multi-stage biochemical process in which protein molecules are dissolved from the aggregates. Researchers at the Center for Molecular Biology of Heidelberg University, the German Cancer Research Center and the Heidelberg Institute for Theoretical Studies collaborated on the project, along with other scientists from Germany, the USA and Switzerland. The results of their research were published in “Nature”.

Proteins in all cells – from bacteria to human – are folded in their native state. Proteins are first manufactured as long, sequential chains of amino acids and must assume a specific three-dimensional structure, i.e., fold, to be functional. This correctly folded state, or protein homeostasis, is at constant risk from external and internal influences. Damaged proteins lose their structure, unfold and then tend to clump together.

“If such aggregates form, they can damage the cells and even cause the cells to die, which we see in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and even in ageing processes,” explains Prof. Dr. Bernd Bukau, Director of the Center for Molecular Biology of Heidelberg University (ZMBH), who is also a researcher at the German Cancer Research Center (DKFZ).

Prof. Bukau explains that damaged proteins do not only clump during the ageing process. Protein aggregates can also occur through changes in the protein structure due to mutation or chemical or environmental stresses. A change in growth conditions, such as an increase in ambient temperature, can cause proteins to lose their structure and unfold. “The formation of protein aggregates in different organs of the human body is associated with a large number of diseases, including metabolic disorders,” explains the ZMBH Director.

The researchers report that very little was known about how our natural defences reverse the process of protein aggregation so effectively in young healthy cells. “Dissolving protein aggregates is a critical step in recycling defective proteins and providing protection against stress-induced cell damage. We had several clues as to the main players in this process, but we didn’t know exactly how it worked,” says lead investigator Dr. Nadinath Nillegoda, a member of Prof. Bukau’s team. The researchers succeeded in identifying a previously unknown, multi-component protein complex that efficiently solubilizes stress-induced protein aggregates in vitro.

This complex consists of molecular folding helpers, the chaperones, which in this case belong to the heat shock protein 70 (Hsp70) class. These are proteins that aid other proteins in the folding process. The Heidelberg researchers also studied the co-chaperones that regulate Hsp70 activity in the protein complex. According to Prof. Bukau, the co-chaperones of the so-called J-protein family are key, in that they “lure” the Hsp70 folding helpers to the protein aggregates and activate them precisely at their target. “The key finding of our work is that two types of these J-proteins must dynamically interact to maximally activate the Hsp70 helper proteins to dissolve the protein aggregates. Only this launches the potent cellular activity to reverse these aggregates.”

Scientists from the Heidelberg Institute for Theoretical Studies (HITS) performed the computational data analysis for this research. For the experimental design and integrating the data from a range of experiments, they developed a special modelling methodology for protein-protein docking to simulate the formation of chaperone complexes. HITS research group leader Prof. Dr. Rebecca Wade, who also conducts research at the ZMBH, notes that this molecular-level modelling was essential for understanding the dynamic interactions underlying the coordinated activity of the two types of J-proteins in the chaperone complex.

According to Prof. Bukau, now research is faced with the challenge of understanding the physiological role and the potential of the newly discovered mechanism well enough to apply these findings from basic research and develop novel strategies for therapeutic interventions. In addition to scientists from the ZMBH, DKFZ and HITS, researchers from the Leibniz Institute for Molecular Pharmacology in Berlin, the Northwestern University in Illinois (USA) and the Swiss Federal Institute of Technology in Zurich (Switzerland) also participated in the work.

Original publication:
N. B. Nillegoda, J. Kirstein, A. Szlachcic, M. Berynskyy, A. Stank, F. Stengel, K. Arnsburg, X. Gao, A. Scior, R. Aebersold, D. L. Guilbride, R. C. Wade, R. I. Morimoto, M. P. Mayer and Bernd Bukau: Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature (published online 5 August 2015), doi:10.1038/nature14884

Contact:
Prof. Dr. Bernd Bukau
Centre for Molecular Biology of Heidelberg University
Phone: +49 6221 54-6850
direktor@zmbh.uni-heidelberg.de

Communications and Marketing
Press Office, phone: +49 6221 54-2311
presse@rektorat.uni-heidelberg.de

Weitere Informationen:

http://www.zmbh.uni-heidelberg.de/bukau/default.shtml

Marietta Fuhrmann-Koch | idw - Informationsdienst Wissenschaft

Further reports about: Biology Cells Molecular Molecular Biology aggregates protein complex proteins

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>