Prion protein NMR structure and species barrier for prion
diseases.

Billeter M, Riek R, Wider G, Hornemann S, Glockshuber R, Wuthrich K

Institut fur Molekularbiologie und Biophysik, Eidgenossische Technische Hochschule, CH-8093
Zurich, Switzerland.

The structural basis of species specificity of transmissible spongiform encephalopathies, such as bovine
spongiform encephalopathy or "mad cow disease" and Creutzfeldt-Jakob disease in humans, has been
investigated using the refined NMR structure of the C-terminal domain of the mouse prion protein
with residues 121-231. A database search for mammalian prion proteins yielded 23 different sequences
for the fragment 124-226, which display a high degree of sequence identity and show relevant amino
acid substitutions in only 18 of the 103 positions. Except for a unique isolated negative surface charge
in the bovine protein, the amino acid differences are clustered in three distinct regions of the
three-dimensional structure of the cellular form of the prion protein. Two of these regions represent
potential species-dependent surface recognition sites for protein-protein interactions, which have
independently been implicated from in vitro and in vivo studies of prion protein transformation. The
third region consists of a cluster of interior hydrophobic side chains that may affect prion protein
transformation at later stages, after initial conformational changes in the cellular protein.

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