Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Oxidation sets off fatal structural change of human prion proteins

23.04.2009
Prion diseases like the Creutzfeldt-Jakob disease mainly appear spontaneously in humans. They are characterized by the aggregation of a misfolded isoform of the cellular prion protein. Scientists at the Max Planck Institute of Biochemistry and the LMU Munich have now uncovered the cause of the misfolding: an oxidation within the prion molecule.

Prion diseases can be sporadic, inherited and infectious. The vast majority (85 percent) of prion diseases in humans can be attributed to a spontaneous structural conversion of the cellular prion protein: Originally dominated by alpha-helices as structural elements, the prion protein is transformed into its misfolded "scrapie" isoform which is dominated by accordion-like folded protein sheets, so called beta-sheets. This changes its chemical properties: The molecule becomes less water-soluble and has a strong aggregation tendency.

"Once there is a misfolded and aggregated prion protein present in the tissue, a chain reaction is triggered where one protein after another changes its shape, like dominos knocking over each other", says Professor Armin Giese (Center for Neuropathology and Prion Research, LMU Munich). The initial event in this misfolding cascade was so far widely unknown. Now the scientists have identified an oxidation within the prion protein as the cause of the structural conversion: "Although other mechanisms are also discussed, we are convinced that the oxidation of the amino acid methionine within the prion protein plays a key role", reports PD Dr. Nediljko Budisa, the head of the research group "Molecular Biotechnology"at the Max Planck Institute.

While the hydrophobic methionine usually stabilizes alpha-helices effectively, its oxidized form supports the structural conversion into beta-sheets. If the oxidative stress within the cell is sufficient enough to oxidise certain methionine molecules within the prion protein, an irreversible process with serious consequences starts: "The prion protein gets literally pushed apart because of the oxidation", says Budisa, "obviously this is devastating for the folding".

To prove these findings conclusively the scientists used an elegant trick: The methionine molecules were replaced with isosteric, chemically stable, non-oxidizable analogs, i.e. with the more hydrophobic norleucine (simulates non-oxidized methionine) and the highly hydrophilic methoxinine (simulates oxidized methionine). "In this way, we created artificial prion proteins, which, like Yin and Yang, reflect two extreme conditions: One prion, that contains non-oxidized methionine molecules only, and one in which all methionine molecules are oxidized", explains Budisa. The norleucine variant resulted in an alpha-helix rich protein that lacks the in vitro aggregation protein of the parent protein. In contrast, the methoxinine variant resulted in a beta-sheet rich protein with strong aggregation tendency.

These results support a correlation of oxidative stress in cells and the misfolding of proteins. They are highly relevant not only for prion research, but also for other neurodegenerative diseases that are associated with protein misfolding. Research in this field is of general importance, because it can give new insights in neurodegenerative diseases and help with the development of new therapeutic strategies.

Original publication:
C. Wolschner, A. Giese, H. Kretzschmar, R. Huber, L. Moroder, N. Budisa: Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein. Proceedings of the National Academy of Sciences USA, Early Edition (April 2009)

doi 10.1073/PNAS.0902688106

Contact:
PD Dr. Nediljko Budisa
Molecular Biotechnology
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried
budisa@biochem.mpg.de
Dr. Monika Gödde
Public Relations
Max Planck Institute of Biochemistry
An Klopferspitz 18
82152 Martinsried
Tel. ++49/89-8578-3882 / 8578-2040
goedde@biochem.mpg.de

Dr. Monika Gödde | idw
Further information:
http://www.biochem.mpg.de/budisa/

More articles from Life Sciences:

nachricht Could this protein protect people against coronary artery disease?
17.11.2017 | University of North Carolina Health Care

nachricht Microbial resident enables beetles to feed on a leafy diet
17.11.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

NASA detects solar flare pulses at Sun and Earth

17.11.2017 | Physics and Astronomy

NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures

17.11.2017 | Health and Medicine

The importance of biodiversity in forests could increase due to climate change

17.11.2017 | Studies and Analyses

VideoLinks
B2B-VideoLinks
More VideoLinks >>>