Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanism to Repair Clumped Proteins Explained

21.11.2012
Heidelberg researchers uncover the function of specific molecular chaperones

Clumped proteins can be dissolved with the aid of cellular repair systems – a process of critical importance for cell survival especially under conditions of stress. Heidelberg researchers have now decrypted the fundamental mechanism for dissolving protein aggregates that involves specific molecular chaperones.


Mechanism of protein aggregate dissolution through Hsp70/Hsp100 cooperation. The ring-shaped Hsp100 has two structural states, one inactive and the other activated. A molecular switch keeps the Hsp100 chaperone in the inactive state. Hsp70 causes the switch to flip, thereby activating the Hsp100 chaperone. In this state it can pull protein strands out of the aggregate. The activation of Hsp100 is not permanent, with the chaperone reverting to the inactive state after the aggregate has dissolved.

Picture credits: ZMBH

Scientists from the Center for Molecular Biology of Heidelberg University and the German Cancer Research Center cooperated with experts from the Heidelberg Institute for Theoretical Studies on the project. The results of the research appeared in two simultaneously published articles in “Nature Structural & Molecular Biology”.

Proteins consist of long chains of successive amino acids and perform vital functions in every cell. To function, every amino acid chain must first assume a specific three-dimensional structure – it has to fold itself. A change in growth conditions, such as an increase in ambient temperature, can cause proteins to lose their structure and unfold. Unfolded protein chains run the risk of clumping, forming protein aggregates. “If such aggregates form, the proteins cannot function, which can lead to cell death, 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).

But clumping does not necessarily mean the end of a protein’s life cycle. “Cells have repair systems for damaged proteins, so-called molecular chaperones, that can dissolve even aggregated proteins and refold them”, clarifies Dr. Axel Mogk, also a member of the ZMBH and DKFZ. The repair is carried out by a cooperating team of two chaperones, called Hsp70 and Hsp100. The Heidelberg researchers were able to demonstrate that the activity of the Hsp100 chaperone is regulated by a built-in molecular switch.
This switch is first positioned to curtail energy consumption, i.e. ATP hydrolysis, and thereby the activity of the Hsp100 chaperone. The cooperating Hsp70 protein changes the position of the switch and activates Hsp100 directly at the protein aggregate. In this state, the “motor” of the ring-shaped Hsp100 protein runs at full speed, reaches top performance and is able to extract individual chains from the aggregate. Afterwards, the extracted, unfolded protein can start the folding process over. The results of the Heidelberg research also show that the built-in switch’s control of Hsp100 activity is of vital importance for this complicated protein machine, because the loss of regulation in hyperactive, i.e. permanently activated, Hsp100 protein variants leads to cell death.

The research collaboration falls under the DKFZ-ZMBH Alliance, the strategic cooperation of the German Cancer Research Center and the Center for Molecular Biology of Heidelberg University. The Heidelberg Institute for Theoretical Studies (HITS) develops new theoretical approaches to interpreting the burgeoning amount of experimental data.

Original publications:

F. Seyffer, E. Kummer, Y. Oguchi, J. Winkler, M. Kumar, R. Zahn, V. Sourjik, B. Bukau & A. Mogk: Hsp70 proteins bind Hsp100 regulatory M domains to activate AAA+ disaggregase at aggregate surfaces, Nature Structural & Molecular Biology, 18 November 2012, doi: 10.1038/nsmb.2442

Y. Oguchi, E. Kummer, F. Seyffer, M. Berynskyy, B. Anstett, R. Zahn, R.C. Wade, A. Mogk & B. Bukau: A tightly regulated molecular toggle controls AAA+ disaggregase, Nature Structural & Molecular Biology, 18 November 2012, doi: 10.1038/nsmb.2441

Contact:

Prof. Dr. Bernd Bukau, Dr. Axel Mogk
Center for Molecular Biology of Heidelberg University
Phone: +49 (0)6221 54-6850, direktor@zmbh.uni-heidelberg.de
Phone: +49 (0)6221 54-6863, a.mogk@zmbh.uni-heidelberg.de

Communications and Marketing
Press Office, phone: +49 (0)6221 54-2311
presse@rektorat.uni-heidelberg.de

Marietta Fuhrmann-Koch | idw
Further information:
http://www.uni-heidelberg.de

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
21.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Nagoya physicists resolve long-standing mystery of structure-less transition

21.08.2017 | Materials Sciences

Chronic stress induces fatal organ dysfunctions via a new neural circuit

21.08.2017 | Health and Medicine

Scientists from the MSU studied new liquid-crystalline photochrom

21.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>