In their malformed variant, prions appear to induce human Creutzfeld-Jacob disease, and BSE, "mad cow" disease. The research team is supported by the Swiss National Science Foundation. Their work attracted attention a year ago when they published a first part of the structure. The research results to be published on Thursday in the review FEBS Letters indicate that the newly decoded part of the protein structure might play an important role in the conversion of the normal prion protein into its disease-inducing variant.
Prion proteins are chains of proteins normally present in the bodies of humans and animals. They cause disease only when they are folded in a particular way-luckily a very rare occurrence so far. The disease-inducing prions appear to contain clumps of several prion protein molecules, which damage the brain of affected humans or animals. Where and how the clumping occurs has not thus far been clear. Professors Kurt Wuethrich and Rudi Glockshuber, and their research team from the Institute for Molecular Biology and Biophysics at the Swiss Federal Institute of Technology in Zurich have made a further, major contribution to this question. They are the first to fully uncover the complete, three-dimensional structure of the normal prion protein.
Compared with its normal form, prion protein isolated from the brains of cows afflicted with BSE has a higher proportion of so-called beta-sheet-containing folds. This is where clumping may occur in the prion protein. Their studies have led the research team in Zurich to the discovery of a part in the molecule which consists of 98 amino acid residues. In the normal prion protein this part is mobile and attached like a flexible tail to the structure described a year ago, the so-called C-terminal domain PrP (121-231). In protein material from animals afflicted with scrapie or BSE a large part of this "tail" of amino acids is not mobile but part of the rigid molecule structure. According to Wuethrich and Glockshuber, these "results indicate that the conversion of the normal to the disease-inducing form of the prion protein may occur much more easily than has been assumed so far, by way of a new fold in the flexible part of the normal protein."
The publication a year ago of the three-dimensional structure of the C-terminal domain PrP (121-231) of the normal prion protein caused a great stir among the public and the experts. The results being published now both confirm and go beyond those findings. They demonstrate that the structure described then is indeed part of the whole protein. What is new is the discovery that the entire remainder of the molecule is not folded, and highly flexible. Both results are a further step towards a deeper understanding of prion diseases. They will be useful in planning future biochemical and biomedical studies.
Further information:
Prof. Kurt Wüthrich, Institut für Molekularbiologie und
Biophysik, ETH-Hönggerberg, 8093 Zürich
Tel. +41 (0)1 633 24 73; Fax: +41 (0)1 633 11 51
Swiss National Science Foundation, M. Iten, Head of Press and Information
Service
Wildhainweg 20, CH-3001 Berne, Switzerland
Tel. +41 (0)31 308 22 22, Fax: +41 (0)31 308 22 65
E-mail: iten@snf.ch, Website: http://www.snf.ch
Legend: A team of researchers from the Institute for Molecular Biology and Biophysics at the Swiss Federal Institute of Technology in Zurich are the first to successfully decode the three-dimensional structure of an intact prion protein.
Their studies have led them to the discovery of a highly flexible part in the molecule which consists of 98 amino acid residues. In the normal prion protein this part is attached like a flexible tail to the structure described a year ago, the so-called C-terminal domain PrP(121-231). This newly decoded part of the protein structure might play an important role in the conversion of the normal prion protein into its disease-inducing variant. The pictures illustrate in two different ways the already known C-terminal domain PrP(121-231) and the recently discovered flexible part of the molecule.
Two colour pictures are available on Internet as postscript (.ps) or Portable Data Format (.pdf) files. The address is ftp://www.snf.ch/Pub/Prion
Journal
FEBS Letters