Prion Protein NMR Structures of Elk and of Mouse/Elk Hybrids

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, ePrPChas the same global fold as other mammalian prion proteins (PrPs), with a flexi...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 3; pp. 646 - 650
Main Authors Gossert, Alvar D., Bonjour, Sophie, Lysek, Dominikus A., Fiorito, Francesco, Wüthrich, Kurt
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 18.01.2005
National Acad Sciences
Subjects
Amino acids
Animals
Atoms
Biological Sciences
Cervidae
Creutzfeldt Jakob syndrome
Elks
Epitopes
Humans
Hydrogen bonds
Mammals
Mice
Mutation, Missense
Nuclear Magnetic Resonance, Biomolecular
Prion diseases
Prions
Prions - chemistry
Prions - genetics
Protein Conformation
Protein Structure, Secondary
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Ruminants
Species Specificity
Spongiform encephalopathies
Structural Homology, Protein
Ungulates
Wasting Disease, Chronic - etiology
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Summary: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, ePrPChas 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 α-helices and a short antiparallel β-sheet. However, ePrPCshows 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 β-sheet with the α2-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 ePrPCrelates 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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Contributed by Kurt Wüthrich, December 6, 2004
Data deposition: The coordinates of ensembles of the 20 conformers have been deposited in the Protein Data Bank, www.pdb.org {PDB ID codes 1XYW [ePrP(121–231)], 1XYX [mPrP(121–231)], 1Y15 (mPrP[N174T]), and 1Y16 (mPrP[S170N,N174T])}.
A.D.G. and S.B. contributed equally to this work.
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.
Abbreviations: PrP, prion protein; PrPC, cellular form of PrP; ePrP, elk PrP; hPrP, human PrP; bPrP, bovine PrP; mPrP, mouse PrP; shPrP, Syrian hamster PrP; CWD, chronic wasting disease; TSE, transmissible spongiform encephalopathy; NOE, nuclear Overhauser effect.
To whom correspondence should be addressed. E-mail: wuthrich@mol.biol.ethz.ch.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409008102