PRION PROTEIN NMR STRUCTURE AND SPECIES BARRIER FOR PRION DISEASES

The structural basis of species specificity of transmissible spongifor m encephalopathies, such as bovine spongiform encephalopathy or ''mad cow disease'' and Creutzfeldt-Jakob disease in humans, has been invest igated using the refined NMR structure of the C-terminal domain of the mouse prion protein with residues 121-231. A database search for mamm alian prion proteins yielded 23 different sequences for the fragment 1 24-226, which display a high degree of sequence identity and show rele vant amino acid substitutions in only 18 of the 103 positions. Except for a unique isolated negative surface charge in the bovine protein, t he amino acid differences are clustered in three distinct regions of t he three-dimensional structure of the cellular form of the prion prote in. Two of these regions represent potential species-dependent surface recognition sites for protein-protein interactions, which have indepe ndently been implicated from in vitro and in viva studies of prion pro tein transformation. The third region consists of a cluster of interio r hydrophobic side chains that may affect prion protein transformation at later stages, after initial conformational changes in the cellular protein.