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Spatial Molecular Structure of the Bovine Prion Protein Decoded at the ETH Zurich

July 11, 2000

The healthy prion proteins of humans and bovine cattle are very similar. It therefore appears, that transmission of Mad Cow Disease (BSE) to humans might be rationalized on the level of the molecular structure. This is reported by a research team from the Institute for Molecular Biology and Biophysics of the ETH Zurich (The Swiss Federal Institute of Technology) in the latest issue of the journal «Proceedings of the National Academy of Sciences» (PNAS). In this work the ETH researchers describe, for the first time, the spatial structure of the bovine prion protein in its normal, healthy form. Differences between the proteins of man and cow are shown only in the distribution of the electrostatic surface charge, but not in the spatial folding of the protein. The Zurich team is also supported by the Swiss National Science Foundation (Schweizerischer Nationalfonds).

Up to the end of 1999 about 50 persons, mainly in Great Britain, had died of the so-called new variant of Creuzfeldt-Jakob disease (nvCJD). Scientists believe that this disease could be caused by the consumption of certain meat products from cattle with BSE. Although laboratory ex-periments could so far not provide unambiguous evidence that mad cow disease can be transmitted to humans through food uptake, the cases diagnosed as nvCJD over the past few years indicate that such transmission does indeed occur. That prion diseases can be transmitted through the food chains is in fact proved by mad cow disease itself: The BSE epidemic was caused in the Eighties because cattle were receiving feed that had been produced from, among other things, prion-infected animal organs.
The question, whether BSE can be transmitted to humans, is the subject of intense discussion among scientists and has far-reaching consequences for the safety of foodstuffs.

The so-called prion protein is involved in the development of both mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. This protein occurs naturally in mammals; it can, however, be transformed into a pathogenic variant that can be precipitated in clumped form in the brain. In order to be able to understand how mad cow disease or Creutzfeldt-Jakob disease develop, it is essential to have a profound knowledge of the prion proteins. Since present information on prion diseases is based largely on animal experiments with mice and hamsters, the prion proteins of these two laboratory species are also of great interest.


Prion proteins of mice, bovine cattle and humans decoded in Zurich
For several years, research teams from the Institute for Molecular Biology and Biophysics of the ETH Zurich, under the direction of Professor Kurt Wüthrich and Professor Rudolf Glockshuber, have been providing important results in this field, which have aroused great interest world-wide. So far, the Zurich researchers have been able to describe the three-dimensional molecular structure of the whole prion protein of mouse and man. The structure of the prion protein of the hamster has also recently been described in the USA. Dr. Francisco L'³pez Garc'­a, Dr. Ralph Zahn, Dr. Roland Riek and Professor Kurt Wüthrich have now decoded the structure of the prion protein of bovine cattle, as they have reported in the renowned journal, PNAS (Proceedings of the National Academy of Sciences"). For the decoding of the spatial structure of the prion proteins, this research team has used the method for the determination of protein structure by means of nuclear magnetic resonance spectroscopy (NMR). This method has been developed in the same institute of the ETH Zurich.

Comparison of the four prion proteins shows that they display very similar three-dimensional folds of the polypeptide chain. The three-dimensional folds of the prion proteins of bovine cattle and humans are in fact practically identical. There are, however, clearly definable local differences in the structures of the prion proteins of the mouse and the hamster on the one hand and those of the cow on the other.


Distribution of the electrostatic charge leads to a new trail
Prion proteins are made up of a freely-mobile tail and a globular, highly structured region containing three spiral segments (alpha helices) and a so-called beta-sheet (Figure 1). The publication in the PNAS now shows that the globular region has practically identical folds in the prion proteins of cow and man while the proteins of the mouse and the hamster show local structural differences relative to the bovine prion protein (Figure 2). These concern in particular regions of the molecule that have previously been implicated to play an important role in the develop-ment of prion diseases.
Differences between the prion proteins of humans and bovine cattle occur in the electrostatic surface charge distribution of the globular region (Figure 3). According to the Zurich team, an influence of the molecular structure of the healthy prion protein on a barrier to the transmission of prion diseases between cow and man could therefore be primarely rationalised by this difference in the surface charge.

There is thus a clear delineation of the ways by which the structure of the healthy prion protein could contribute to the creation of an inter-species barrier to the transmission of prion diseases. In the long term, this observation could lead to new possibilities for influencing and possibly preventing the transmission of prion-dependent diseases between different mammalian species.

Zurich, 10 July 2000 / AOA 53 / KW











For further information please contact:

Prof. Kurt Wüthrich
Institut für Molekularbiologie und Biophysik
ETH-Hönggerberg
CH-8092 Zürich
Tel: +411 633 24 73      Fax: +411 633 11 51
E-mail: wuethrich@mol.biol.ethz.ch








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