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.
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
Prof. Dr. Bernd Bukau
Centre for Molecular Biology of Heidelberg University
Phone: +49 6221 54-6850
Communications and Marketing
Press Office, phone: +49 6221 54-2311
Marietta Fuhrmann-Koch | idw - Informationsdienst Wissenschaft
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction