Proposed three-dimensional structure for the cellular prion protein.

Abstract

Prion diseases are a group of neurodegenerative disorders in human and animals that seem to result from a conformatlonal change in the prion protein (PrP). Utilizing data obtained by circular dichroism and in spectroscopy, computational studies prdIe the tedi nal s ture of the cellular form of PrP (PrPC). A heuristic approach consistng of the prediction of so structures and of an evalnation of the pig of s y elements was used to search for plausible teriay strucures. After a series of experimental and theoretical ants were applied, four structural models of four-helix bundles emerged. A group of amino acids within the four predicted helices were Identified as important for tertiary interactions between helices. These amino acids could be essential for ma ining a stable tertiary suture of PrPC. Among four plausible s al models for PrPC, the X-bundle model seemed to correlate best with 5 of 11 known point mutations that segregate with the inherited prion diseases. These 5 mutions cluster around a central hydrophobic core in the X-bundle structure. Furthermore, these mutations occur at or near those amino acds which are predicted to e important for helix-helix interactions. The three-dimensonal structure of

Metal‐dependent α‐helix formation promoted by the glycine‐rich octapeptide region of prion protein

“…The octapeptide in PrP c may be a novel structural motif that acts as a promoter of the a-helix formation. The peptide segment corresponding to PrP(84-103) is in close proximity to the putative first helix region (residues 109 122) of a four-helix-bundle model proposed for the Cterminal region of PrP c [8] (see Fig. 1).…”

“…Mature human PrP c after post-translational modifications spans residues 23 231 of the 253 amino acid residues coded by a single gene [5][6][7]. A molecular modeling study suggested that the C-terminal half of PrP C may form a bundle of four ¢x-helices at residues 109 122 (HI), 129 141 (H2), 178-191 (H3), and 202-218 (H4) [8] (Fig. 1).…”

“…The aggregated PrP sc acquires resistance to proteolytic degradation and causes fatal neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy in animals and Creutzfeld-Jakob disease in humans [2]. Although the c~-helix-to-[3-sheet transition in the C-terminal half region may be related to the PrP c ~ PrP sc transformation [8,11,12], the molecular mechanism of the conformational transition has not yet been clarified.…”

“…1). Because of its glycine-and proline-rich amino acid sequence, neither c~-helix nor [3-sheet structure has been predicted in this region [8]. The protein found in the PrP sc amyloid, sometimes designated PrP 27-30, lacks the N-terminal region due to proteolytic truncation and it is considered that the N-terminal region is not directly related to the amyloid formation [13].…”

Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation

“…Four of these residues are close to the glycosylphosphatidylinositol anchor attached to Ser-231 whereas the remaining three residues lie within the C-terminal ␣-helix (18)(19)(20). We reasoned that replacement of Mo residues with Hu counterparts at these positions would inhibit PrP Sc formation given the previous evidence for the species specific preferences for protein X (5).…”