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Cholesterol transporter structure decoded

21.03.2014

The three-dimensional structure of the transport protein TSPO opens up novel paths for the diagnosis and treatment of brain diseases


The cholesterol transporter TSPO in the outer mitochondrial membrane serves as a docking site for important diagnostic markers and for a number of drugs such as diazepam. Source: Łukasz Jaremko, Mariusz Jaremko, Markus Zweckstetter / DZNE, Max Planck Institute for Biophysical Chemistry and UMG

Joint press release of the DZNE and Max Planck Institute for Biophysical Chemistry

The word "cholesterol" is directly linked in most people's minds with high-fat foods, worrying blood test results, and cardiovascular diseases. However, despite its bad reputation, cholesterol is essential to our wellbeing:

It stabilizes cell membranes and is a raw material for the production of different hormones in the cell’s power plants – the mitochondria. Now, for the first time, scientists in Göttingen have solved the high-resolution structure of the molecular transporter TSPO, which introduces cholesterol into mitochondria.

This protein also serves as a docking site for diagnostic markers and different drugs, such as Valium. The detailed knowledge of its three-dimensional shape and function opens up new diagnostic and therapeutic perspectives.

Not only are mitochondria the most important energy supplier in living cells. They also produce steroid hormones such as testosterone and oestradiol, which control many processes in the body. The raw material for the production of steroid hormones is cholesterol, which must first be transported into mitochondria across two membranes.

This difficult task is carried out by a molecular transport protein named TSPO in the outer mitochondrial membrane. Using nuclear magnetic resonance spectroscopy, two teams working with the Göttingen-based scientists Markus Zweckstetter and Stefan Becker have now shown the complex three-dimensional structure of the protein “at work” in atomic detail.

The researchers achieved this methodical breakthrough by applying an ingenious trick: In their experiments, they coupled the transporter to an important diagnostic marker called PK11195; it was this complex that first gave the scientists analyzable results. In fact, the TSPO structure delivers more than just clues about how cholesterol is transported into the mitochondria.

"We now also have a much better understanding of how TSPO recognizes and binds to diagnostic markers and drugs", explains Markus Zweckstetter, head of research groups at the German Center for Neurodegenerative Diseases (DZNE), at the Max Planck Institute for Biophysical Chemistry, and at the Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) at the University Medical Center of Göttingen (UMG).

TSPO has long been successfully used in diagnostics and treatment of a number of diseases. "When the brain is injured or inflamed, its cells produce more TSPO. This fact is used in the diagnosis of neurodegenerative diseases such as Parkinson's and Alzheimer's", explains Stefan Becker, a protein chemist and Max Planck researcher who works next door to Zweckstetter.

Physicians also use radioactively tagged molecules such as PK11195 to visualize inflamed areas of the brain. A detailed understanding of how TSPO binds to such markers opens up novel paths for diagnostic imaging and could constitute an important step along the way to early detection of such diseases and inflammations.

TSPO also binds several medicinal drugs such as diazepam, also known by the trade name of Valium. Not only is diazepam a widely prescribed sedative; it is also used in the treatment of anxiety and epileptic seizures. The Göttingen researchers hope that detailed information about the transporter’s structure will help to develop new TSPO-binding drugs.

Original publication
Łukasz Jaremko, Mariusz Jaremko, Karin Giller, Stefan Becker, Markus Zweckstetter. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science 21 March 2014: Vol. 343 no. 6177 pp. 1363-1366 DOI: 10.1126/science.1248725

Contact
Prof. Dr. Markus Zweckstetter
Research Group Structural Biology in Dementia
German Center for Neurodegenerative Diseases (DZNE)
Research Group Structure Determination of Proteins Using NMR
Max Planck Institute for Biophysical Chemistry
University Medical Center Göttingen
+49 551 201-2220
markus.zweckstetter(at)dzne.de

Dr. Stefan Becker
Project Group Molecular Biology
Department of NMR-based Structural Biology
Max Planck Institute for Biophysical Chemistry
+49 551 201-2222
sabe(at)nmr.mpibpc.mpg.de

Dr. Carmen Rotte
Press and Public Relations
Max Planck Institute for Biophysical Chemistry
+49 551 201-1304
crotte(at)gwdg.de

Dr. Marcus Neitzert
Press and Public Relations
German Center for Neurodegenerative Diseases (DZNE)
+49 43302-271
marcus.neitzert(at)dzne.de

www.dzne.de

Markus Zweckstetter | EurekAlert!

Further reports about: Biology Biophysical DZNE Molecular Valium cholesterol diseases drugs mitochondrial protein

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