It is still unknown why this misfolding occurs. The first stages of folding and the onset of the aggregation of the proteins, the so-called oligomerisation, appear to be decisive for pathogenesis.
The Research teams of Prof. Klaus Gerwert and Prof. Detlev Riesner in Bochum and Düsseldorf have now been able to observe the proteins in their natural environment. They investigated the structural changes of the prion protein (PrP), the trigger for Creutzfeldt-Jacob Disease, by anchoring it to a cell membrane. As summarized by Prof. Gerwert, “Much to our surprise, the reaction of a membrane-anchored prion protein differs from that of a PrP in solution.
Unstructured parts of the protein fold in a manner that makes it easy for another prion protein to be adsorbed – the possible onset of the pathogenetic structure.” The results of this research work are available online in the current edition of the Proceedings of the National Academy of Science (PNAS).
Abnormal folding in replication
The prion protein is physiologically well-folded in a healthy organism, particularly within the central nervous system. If prion proteins refold, they can change into abnormally structured, infectious prion proteins. Insoluble deposits within the cells, so-called amyloid structures, which ultimately lead to the dissolution of the affected cells, gradually develop. Amyloid diseases are almost always fatal.
The binding of membranes changes the behaviour of the prions
Gerwert and Riesner are the first scientists who have been able to reproduce the situation in living cells by analyzing membrane-anchored prion proteins. They were surprised to discover that there is a difference between the behaviour of the membrane-anchored protein at the membrane and the un-bound membrane in solution, which had been the focal point of all biophysical research work to date.
The Nobel Prize Winner Kurt Wüthrich had also determined the three-dimensional structure of the prion protein on unanchored prion proteins. To cite Prof. Gerwert, “High concentrations of prion protein at the membrane result in unstructured parts of the prion protein folding in a manner that makes it easy for numerous prion proteins to be adsorbed.
So-called beta sheets, comparable with two corrugated iron sheets, develop, enabling easy and perfectly fitting anchorage of the proteins.” The folding thus appears to induce the oligomerisation and possibly also the pathogenetic structure. To date, the structure of fully glycosylated prion proteins at the membrane has not been described in research reports.
Infrared spectroscopy identifies the folding
This new information could be gained by interdisciplinary cooperation of the two research teams. The team from Düsseldorf has already presented many important reports on prion research in the past. The studies on the folding of the membranes were then performed in Bochum. A new method was introduced: the prion protein was anchored to a membrane that was placed on an ATR (attenuated total reflectance) crystal.
The folding was then analyzed by infrared spectroscopy. “If an infrared ray passes through the ATR crystal, part of the radiation penetrates into and is absorbed by the attached sample,” explained Prof. Gerwert. “The absorption is just as unique for a protein structure as a fingerprint is for a human being.” In the infrared spectrum, every protein structure creates its own pattern. Changes therein are direct signs of a folding procedure.
Prof. Dr. Klaus Gerwert | alfa
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