Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Trembling hands and molecular handshakes

26.10.2009
A novel protein structure involved in hereditary neurodegeneration

Fragile X tremor/ataxia syndrome (FXTAS) is a recently recognized condition, which is actually one of the most prevalent heritable neurodegenerative diseases. It is assumed that the condition is caused by deficiency for the protein Pur-alpha, which is essential for normal neural function.

Structural studies undertaken by a team under the leadership of Dr. Dierk Niessing of the Helmholtz Zentrum München and the Gene Center at Ludwigs-Maximilians-University (LMU) have now determined the three-dimensional structure of Pur-alpha, and gained insights into the molecular function of the protein. The findings provide a possible basis for the development of an effective therapy for the disease.(PNAS Early Edition, 21. Oktober 2009)

Most FXTAS patients are males, and symptoms of the condition become manifest around the age of 55. As the disease progresses, patients develop tremor in their hands and also show ataxia, i.e. they have difficulty maintaining their balance when they move, and therefore have a tendency to fall. Quite often these deficits are accompanied by cognitive defects and dementia.

The underlying cause of FXTAS is a mutation in the gene for FMRP (Fragile X Mental Retardation Protein). This mutation is found on the X chromosome in one out of 800 men, and involves abnormal expansions of a DNA sequence composed of repeats of the base triplet CGG. Healthy people have between 5 and 54 copies of this sequence, while those who will develop FXTAS are born with between 55 and 200 repeats. Expansion of the triplet sequence beyond 200 copies leads to Fragile X Syndrome (FXS), which is the second most common cause of hereditary mental retardation after Down's syndrome. FXTAS itself is apparently triggered by a lack of the protein Pur-alpha. This protein binds to the CGG sequences in FMR messenger RNAs (mRNA). The excessive numbers of CGG triplets found in the mutant FMRP mRNA essentially bind so much Pur-alpha that insufficient amounts are available for its normal cellular function.

Dr. Niessing's team reports in the online Early Edition of the journal Proceedings of the National Academy of Sciences USA (PNAS) that the Pur-alpha protein itself consists of three copies of a structural unit called the PUR repeat. "The crystal structure of Pur-alpha will make it possible to understand the protein's function in detail, and this could contribute to the development of a therapy for FXTAS", says Dierk Niessing, who leads a junior research group that is jointly funded by the Helmholtz Zentrum München, the Helmholtz Association and LMU's Gene Center. "With the treatment options we have at the moment, we can only alleviate the symptoms but cannot attack the real cause of the disease."

"A PUR repeat looks like a hand: four so-called beta-strands, corresponding to four fingers, form a beta-sheet, and an adjacent alpha-helix resembles a thumb", explains Almut Graebsch, the first author from Niessing's group. Pairs of PUR repeats bind to each other in a particular configuration that is reminiscent of a handshake, forming a functional unit. In addition to X-ray diffraction, the researchers have used a technique called small angle X-ray scattering, which revealed that the Pur-alpha protein forms dimers – two molecules of the protein bind stably to one another. This probably occurs when PUR repeats in separate molecules interact, in a similar way to the repeats within a molecule, to form the handshake structure.

Experiments in animals have shown that the symptoms of FXTAS disappear if extra Pur-alpha is supplied. "Perhaps the condition can be cured if one can find a way of stopping Pur-alpha from binding to long stretches of CGG in mRNA", says Niessing. By mutating the protein, his group has already obtained clues to how Pur-alpha binds to the CGG repeats. The next step is to find out precisely how Pur-alpha binds to RNA. This in turn could suggest ways of preventing the interactions that cause the disease. (HHZM)

The Helmholtz Zentrum München

The Helmholtz Zentrum München is the main institution charged with research on health and the environment in Germany. As the leading center for Environmental Health Sciences, it conducts research on chronic and complex diseases, which result from a combination of environmental factors and individual genetic predisposition. The Center employs some 1680 people. The major facility is located on a 50-hectare research campus in Neuherberg, to the North of Munich. The Helmholtz Zentrum München is part of the largest research organization in Germany, the Helmholtz Association, a consortium of 16 technological and biomedical research centres with a combined staff of 26,500.

Scientists at the Institute for Structural Biology use NMR spectroscopy and X-ray diffraction to determine the three-dimensional structures of biologically relevant proteins and nucleic acids, and to probe their behaviour in aqueous solution. By combining insights from structural analyses with biochemical experiments, it is possible to understand the molecular bases of biological function. Efforts are now underway to optimize NMR so that the technique can be applied to larger proteins and protein complexes (consisting of several subunits).

The Gene Center at LMU Munich

The Gene Center at LMU Munich pursues a combination of interdisciplinary research and teaching in key areas of modern bioscience. Its major goal is to elucidate the mechanisms responsible for cell and organismal function under normal and pathological conditions. The basic approach focuses on gene regulation, but methods from structural biology, molecular cell biology, genetics, developmental biology and virology are all exploited in order to decipher the molecular mechanisms that underpin basic biological processes.

Publication:
"X-ray structure of Pur-alpha reveals a Whirly-like fold and an unusual nucleic-acid binding surface"
Almut Graebsch, Stephane Roche, and Dierk Niessing.
PNAS online, 21 October 2009
Contact:
Dr. Dierk Niessing
Institute for Struktural Biology of the Helmholtz Zentrum München and Gene Center of the LMU
Phone: +49 089 / 2180 - 76962
Fax: +49 89 / 2180 - 99-76962
E-Mail: niessing@lmb.uni-muenchen.de

Dr. Dierk Niessing | EurekAlert!
Further information:
http://www.uni-muenchen.de

More articles from Physics and Astronomy:

nachricht APEX takes a glimpse into the heart of darkness
25.05.2018 | Max-Planck-Institut für Radioastronomie

nachricht First chip-scale broadband optical system that can sense molecules in the mid-IR
24.05.2018 | Columbia University School of Engineering and Applied Science

All articles from Physics and Astronomy >>>

The most recent press releases about innovation >>>

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

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

When corals eat plastics

24.05.2018 | Ecology, The Environment and Conservation

Surgery involving ultrasound energy found to treat high blood pressure

24.05.2018 | Medical Engineering

First chip-scale broadband optical system that can sense molecules in the mid-IR

24.05.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>