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.
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.
Swiss National Science Foundation (SNSF)