NMR solution structure of the human prion protein

The NMR structures of the recombinant human prion protein, hPrP(23-230), an d two C-terminal fragments, hPrP(90-230) and hPrP(121-230), include a globu lar domain extending from residues 125-228, for which a detailed structure was obtained, and an N-terminal flexibly disordered "tail." The globular do main contains three alpha-helices comprising the residues 144-154, 173-194, and 200-228 and a short anti-parallel beta-sheet comprising the residues 1 28-131 and 161-164. Within the globular domain, three polypeptide segments show increased structural disorder: i.e., a loop of residues 167-171, the r esidues 187-194 at the end of helix 2, and the residues 219-228 in the C-te rminal part of helix 3. The local conformational state of the polypeptide s egments 187-193 in helix 2 and 219-226 in helix 3 is measurably influenced by the length of the N-terminal tail, with the helical states being most hi ghly populated in hPrP(23-230), When compared with the previously reported structures of the murine and Syrian hamster prion proteins, the length of h elix 3 coincides more closely with that in the Syrian hamster protein where as the disordered loop 167-171 is shared with murine PrP. These species var iations of local structure are in a surface area of the cellular form of Pr P that has previously been implicated in intermolecular interactions relate d both to the species barrier for infectious transmission of prion disease and to immune reactions.