PrP structure

Isoforms

Normal PrPC structure

The normal PrP structure is 253 amino acids long. It includes two signal sequences in the amino- and carboxy- terminal ends which are removed during post-translational modification.

Prion protein contains 5 amino-terminal octapeptide repeats of PHGGGWGQ. This is thought to include a calcium binding domain via nitrogen atoms in the histidine imidazole side chains and deprotonated amide nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind calcium is therefore pH dependent. NMR shows Calcium binding results in conformational change at the N-terminus.

For human and Syrian Hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond exists between Cys179 of the second helix and Cys214 of the third helix (human PrP^C numbering). The protein attaches to the outer surface of the cell membrane by glycosylphosphatidylinositol anchor at its C-terminal Ser231.

pectroscopic analysis

The NMR structure of the full length and N-terminally truncated forms of human PrP prion protein revealed an N-terminal flexible and disordered region PrP23-126 and an orthogonal bundle (OB) structured C-terminal globular domain PrP127-231 (Figure 1). The human PrP globular domain containing three α-helices comprising residues 144-154 (H1), 173-194 (H2), 200-228 (H3) and an anti-parallel β sheet consisting of two short strands comprising residues 128-131 (S1) and 161-164 (S2) . All NMR studies could identify the three alpha helices, although with slightly different length but showed differences for the less defined antiparallel beta sheet.

PrPSc structure

The abnormal form of the PrP protein implicated in TSEs has a different secondary and tertiary structure. Fourier-transform infrared spectroscopy showed that normal PrPC was 43% alpha helical and 3% beta-pleated sheet, whilst abnormal PrPSc was only 30% alpha helical and 43% beta pleated sheet. This suggests a refolding event, and may explain the resistance of the protein to proteolysis.

Polymorphisms in scrapie

Polymorphisms at site 136, 154 and 171 are associated with varying susceptibility to scrapie. Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whilst PrP-ARR is associated with resistance.

The National Scrapie Plan aims to bread out these scrapie polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie so this may prove unfruitful.

References

*citebook|title=Prions: New Research|author=Bridgette V. Doupher|year=2006|publisher=Nova Publishers|id=ISBN 1600210198