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##################### Bovine Spongiform Encephalopathy #####################
Prion protein NMR structures of elk and of mouse/elk hybrids
( transmissible spongiform encephalopathy | chronic wasting disease )
Alvar D. Gossert *, Sophie Bonjour *, Dominikus A. Lysek, Francesco
Fiorito, and Kurt Wüthrich {dagger}
Institut für Molekularbiologie und Biophysik, Eidgenössische Technische
Hochschule Zürich, CH-8093 Zürich, Switzerland
Contributed by Kurt Wüthrich, December 6, 2004
The NMR structure of the recombinant elk prion protein (ePrP), which
represents the cellular isoform (ePrPC) in the healthy organism, is
described here. As anticipated from the highly conserved amino acid
sequence, ePrPC has the same global fold as other mammalian prion
proteins (PrPs), with a flexibly disordered "tail" of residues 23-124
and a globular domain 125-226 with three {alpha} -helices and a short
antiparallel {beta} -sheet. However, ePrPC shows a striking local
structure variation when compared with most other mammalian PrPs, in
particular human, bovine, and mouse PrPC. A loop of residues 166-175,
which links the {beta} -sheet with the {alpha} 2-helix and is part of a
hypothetical "protein X" epitope, is outstandingly well defined, whereas
this loop is disordered in the other species. Based on NMR structure
determinations of two mouse PrP variants, mPrP[N174T] and
mPrP[S170N,N174T], this study shows that the structured loop in ePrPC
relates to these two local amino acid exchanges, so that
mPrP[S170N,N174T] exactly mimics ePrPC. These results are evaluated in
the context of recent reports on chronic wasting disease (CWD) in
captive and free-ranging deer and elk in the U.S. and Canada, and an
animal model is proposed for support of future research on CWD.
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Author contributions: K.W. designed research; A.D.G., S.B., D.A.L., and
F.F. performed research; and A.D.G., S.B., D.A.L., and K.W. wrote the paper.
*A.D.G. and S.B. contributed equally to this work.
{dagger} To whom correspondence should be addressed.
Kurt Wüthrich, E-mail: wuthrich@mol.biol.ethz.ch
www.pnas.org/cgi/doi/10.1073/pnas.0409008102
http://www.pnas.org/cgi/content/abstract/0409008102v1
TSS
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