Is An Anchor Responsible For Mad Cow Disease (BSE) Infections?
ScienceDaily (Nov. 29, 2008) — Chemists at ETH
Click here to view figure: http://www.sciencedaily.com/images/2008/11/081129174042-large.jpg
The prion protein (red structure) is bound
to an anchor made of sugars and a fatty acid that plugs into the lipid bilayer (dark grey circles with appendages) of a cell
membrane, thus anchoring the construct to the surface of the cell. Chemists
Several years ago mad cow disease was the number one topic in the media. Discussion of this disease, which is caused by prion proteins, went quiet some time ago but the case is far from being closed. Just this September, scientists reported a new form of BSE, namely the disease known as BASE. Although this has been known since 2003, researchers discovered only recently that the prion causing BASE can infect primates and possibly humans, with the disease that progresses even faster than BSE.
Infectious process still not understood
Some secrets of prion diseases remain hidden. For example, it is still unclear why the prion, a protein with a relatively simple structure, suddenly changes its configuration and thus causes illness in the host organism, e.g. a cow, sheep or human being.
The researchers suspected the so-called glycosylphosphatidylinositol molecules, abbreviated GPI that are bound to prion proteins. GPIs consist of sugar and fatty acids and anchor prions in the cell surface. This anchoring of prions by GPIs may be responsible for the infection before the prion changes its configuration from harmless to harmful, and makes additional prions fold to cause illness.
A construct that could not be isolated
However, to date the isolation of these complicated anchored prions in their entirety from natural systems was unsuccessful, and researchers had to limit themselves to studying the structure, function, stability and folding of the unusual pathogens without their anchor. In turn that means that the exact function of the GPI anchor could not be determined directly, and “naked” proteins are unable to penetrate cells to start an infection.
This gap has now been filled by the German-Swiss research team led by Peter Seeberger, ETH Zurich Professor for Organic Chemistry, and Christian Becker, Professor at the Protein Chemistry Laboratory of the Technical University of Munich. They have been the first to artificially replicate the molecule complex’s complicated structure in the laboratory. Seeberger’s group synthesised the GPI anchor and Becker’s group the prion. The two substances were then joined together to form the complete entity. Seeberger stresses that “The synthesis of the GPI anchor is a milestone for chemistry. The artificial production of such complicated anchored molecules has, up until now, been unsuccessful.”
A tool supplied
Initial tests show the researchers that they have created the “right” thing. The artificial prion and its GPI can anchor themselves into membranes. This breakthrough means that prion researchers can now at last investigate the role of the GPI anchor and its appended prion in more detail to discover whether the GPI really does have an effect on the folding of the prion and its resulting pathogenic properties. According to ETH Zurich Professor Seeberger: “That will be a task for the prion researchers led by Professor Adriano Aguzzi at the Zurich University Hospital, that received important tools in form of the synthetic prion. “
1. Becker CFW, Liu X, Olschewski D, Castelli R, Seidel R, Seeberger PH. Semisynthesis of a Glycosylphosphatidylinositol-Anchored Prion Protein. Angewandte Chemie International Edition, 2008; 47 (43): 8215 DOI: 10.1002/anie.200802161
Adapted from materials provided by ETH Zurich. Original article written by Peter Rueegg.
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