Les privns Structural biology of priori proteins K. Wiithrich, R. Riek, G. Wider, F. Lo M. Billeter, S. Hornemann, R. Glocks K ez Garcia, A. Liu, R. Zahn, uber 31 Prions are a novel class of infectious pathogens that are distinct from bacteria, viruses or viroids, and in which nucleic acids are apparently not essential for the propagation of the infectious agent. Prion dis- eases, or transmissible spongiform encephalo- pathies (TSE), include scrapie in sheep, bovine spongiform encephalopathy (BSE), and kuru, Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI) and the Gerstmann-straussler- Scheinker syndrome (GSS) in humans. The protein- only hypothesis suggests that onset of TSEs is related to a conformational transition of the ubiqui- tous cellular form of the prion protein in mam- malian tissues, PrP’, into an infectious form, PrP. In the context of the protein-only hypothesis, knowledge of the three-dimensional structures of PrPC and I’rP”’ is of keen interest. Neither of the two forms of the prion protein has so far been crystal- lized, so that nuclear magnetic resonance (NMR) spectroscopy is presently the only technique capable of providing atomic resolution structural data. This approach has been successfully applied with the I’rPc form of the prion protein. NMR structural studies have been performed with recombinant fragments of various lengths from the human, bovine and murine PrPs, including the intact pro- teins comprising residues 23-231 [l-3]. The sepa- rately determined globular structures of the C-ter- minal domains 121-231 were found to be preserved in the intact proteins, and the N-terminal polypep- tide segment 23-120 is flexibly disordered. Struc- tural information has been obtained from experi- ments with the uniformly “N labeled proteins and with ‘%Z, ‘“N-doubly labeled preparations, and is based on nearly complete sequence-specific reso- nance assignments. The linewidths in heteronuclear ‘H-‘“N correlation spectra and i5N{‘H)-NOEs showed that the well structured residues 126-230 have correlation times of several nanoseconds, as is typical for small globular proteins, whereas correla- tion times shorter than 1 nanosecond were observed for all residues outside of this domain. Implications of this structural data for the transition of PrP” to PrPsC will bt>discussed 14-71. References Riek R, Homemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K. NMR structure ot the mouse prion protein domain PrP (121-231). Nature 1996 ; 382 : 180-2. Riek R, Hc~rnemann S, Wider G, Glockshuber R, Wuthrich K. NMR characterization of the full length recombinant murine priori protein, mPrP (23231). FEBS Letters lYY7 ; 413 : 282-8. Zahn I<, van Schroetter C, Wuthrich K. Human prion pro- teins exprc,ssed in t:ciwri&r~ co// and purified by high-affin- ity column refolding. FE&S Letters lYY7 ; 117 : 400-4. Billeter M, Riek R, Wider G, Hornemann S, Glockshuber R, Wuthrich K. Priori protein NMR structure and species bar- rier for prlon diseases. l’roc Nat1 Acad Sci USA lYY7 ; Y4 : 7281-5. Korth (1, Stierli E, Streit I’, Moser Icl, Schaller 0, Fischer R, et al. Priori (Prl“%pecific epitope defined by a monoclonal antibody. Nature 1997 ; 390 : 74-7. Glockshuber R, Hornemnnn S, Billeter M, Riek R, Wider G, Wuthrich K. Priori protein structural features indicate possi- ble relations to signal peptidases. FEBS Letters lYY8 ; 426 : 291-h. Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wuthrich K. I’rion protein NMR structure and familial human spongiform encephalopathies. Proc Nat1 Acad Sci USA 1998 (in press).