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Review
, 6 (10), 3875-92

The Structure of Human Prions: From Biology to Structural Models-Considerations and Pitfalls

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Review

The Structure of Human Prions: From Biology to Structural Models-Considerations and Pitfalls

Claudia Y Acevedo-Morantes et al. Viruses.

Abstract

Prion diseases are a family of transmissible, progressive, and uniformly fatal neurodegenerative disorders that affect humans and animals. Although cross-species transmissions of prions are usually limited by an apparent “species barrier”, the spread ofa prion disease to humans by ingestion of contaminated food, or via other routes of exposure, indicates that animal prions can pose a significant public health risk. The infectious agent responsible for the transmission of prion diseases is a misfolded conformer of the prion protein, PrPSc, a pathogenic isoform of the host-encoded, cellular prion protein,PrPC. The detailed mechanisms of prion conversion and replication, as well as the high-resolution structure of PrPSc, are unknown. This review will discuss the general background related to prion biology and assess the structural models proposed to date,while highlighting the experimental challenges of elucidating the structure of PrPSc.

Figures

Figure 1
Figure 1
Schematic representation of human PrP mutations and polymorphisms. The 0.76 kb ORF of the PRNP gene encodes a 253 amino acid protein, PrPC. Human PrP consist of a cleaved signal peptide (1–22), an octapeptide repeat-containing unfolded domain (OR, 51–91), three α-helices (H1, H2, and H3), one small, antiparallel β-sheet (β1 and β2), and a GPI-anchor signal (232–253). The N-terminal octapeptide repeat motif is comprised of eight residues: P(H/Q)GGG(-/G)WGQ. Normal PrP contains five copies of this motif; a single OR deletion is considered a non-pathogenic polymorphism. However, insertional mutations consisting of one to nine additional OR are pathogenic. Polymorphisms and pathogenic mutations of the PRNP gene are represented above and below the schematic, respectively. Letters preceding the numbers indicate the normal amino acid residue for the position and letters following the numbers designate the new residue.
Figure 2
Figure 2
Organization of human PrP. The unprocessed PrP is 253 amino acid residues in length and includes a signal peptide (1–22), four OR, a hydrophobic region (113–135), one disulphide bond between cysteine residues (179–214), two N-linked glycosylation sites (at residues 181 and 197), and a GPI-anchor attached to the C-terminus of PrP replacing the GPI-anchor signal (residues 232 to 254). The four OR in the N-terminal domain have a high affinity for copper ions (Cu2+), while a preceding nonapeptide (PQGGGGWGQ) lacks the histidine that is necessary to bind a Cu2+ ion. Mutated forms of PrP can contain insertions of one to nine additional OR or a deletion of one OR. A palindromic region, AGAAAAGA (113–120), lies in the hydrophobic region (113–135) and is thought to be important in the conversion of PrPC to PrPSc. OR: Octapeptide repeat; GPI: glycophosphatidylinositol; PK: proteinase K; CHO: carbohydrates.
Figure 3
Figure 3
Schematic diagram of the structure of PrPC. The carbohydrate moieties that are linked to Asn 181 (down) and Asn 197 (up) are shown in pink. The C-terminal GPI-anchor is shown in green and is extending into the cell membrane in blue and red. OR residues in the N-terminal domain are known to bind copper ions (shown in blue). The composite data file for the structure [90,91] was kindly provided by Dr. Glenn Millhauser (University of California, Santa Cruz) and includes coordinates for the carbohydrates, the GPI-anchor, and the membrane that were provided by Dr. Valerie Daggett (University of Washington, Seattle).

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