Structural polymorphism of 441-residue Tau at single residue resolution

February 17, 2009

Press release from PLoS Biology

Worldwide almost 30 million suffer from Alzheimer's disease, an irreversible, neurodegenerative condition that is eventually fatal. The brains of people with Alzheimer's contain two types of misfolded proteins - amyloid plaques and tangles of the protein Tau. Whether these protein abnormalities are a cause of Alzheimer's or a consequence of the disease are unclear. A new paper in this week's PLoS Biology investigates the structure of Tau to better understand its role in healthy cells and in the pathology of Alzheimers.

Tau normally functions by binding to microtubules, the building blocks of the cellular skeleton. Microtubules serve as "tracks" for the transport of material within the cell. In patients afflicted by Alzheimer's disease or similar dementia, tau is abnormally altered - it is more phosphorylated. "Our interest was focussed on how certain phosphorylated residues alter the structure of tau in a way that it can not bind to microtubules anymore," explains Markus Zweckstetter at the Max Planck Institute for Biophysical Chemistry.

The failure of previous attempts to analyse the structure of Tau have made it seem mysterious. Standard methods, such as X-ray crystallography, have not revealed the structure. The breakthrough in analysing the structure comes from using Nuclear Magnetic Resonance spectroscopy. The scientists were able to identify the structural properties of tau and follow its fast motions. For the first time detailed investigations of structural changes from a large almost unfolded protein where conducted.

"We can directly observe which modules of the tau protein bind to microtubules. If the protein is equipped with more phosphates than usual we can see that in this case the binding becomes significantly weaker. Tau and microtubule proteins can no longer interact," summarizes Zweckstetter. As a direct consequence the transport along the microtubule "tracks" is disturbed and nerve cell endings do not grow.

Eckhard and Eva Mandelkow at the Max Planck Unit of Structural Molecular Biology in Hamburg are optimistic in using tau as a pharmaceutical target. Using genetically altered mice, Eva Mandelkow and co-workers were able to show reversibility of the fatal consequences of tau aggregation. Next, scientists hope to investigate which inhibitors interact with the tau protein to prevent fibril formation.

http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.1000034

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