The human prion protein and its normal processing

Sequence of the human prion protein

Significance

manlgcwmlvlfvatwsdlglckkrpkpggwntggsrypgqgspggnryppqggggwgqp

hgggwgqphgggwgqphgggwgqphgggwgqgggthsqwnkpskpktnmkhmagaaaaga

vvgglggymlgsamsrpiihfgsdyedryyrenmhrypnqvyyrpmdeysnqnnfvhdcv

nitikqhtvttttkgenftetdvkmmervveqmcitqyeresqayyqrgssmvlfssppv

illisfliflivg

hPrP^C, the ‘normal’ human protein consists of 253 amino acids and is synthesized from mRNA within the cell, the protein does not remain intact but is processed on its way to the cell surface

Prion protein regions and processing

Significance

manlgcwmlvlfvatwsdlglc

hydrophobic leader sequence removed before sending to cell surface, specific forms of neurodegeneration occur if the leader sequence is not removed and a transmembrane form of the protein results

pqggggwgq-phgggwgq-phgggwgq-phgggwgq-phgggwgq

octapeptide repeats are found within the protein
(5 repeats common, this sequence is involved in binding metal ions, in particular copper)

c

cysteine residues involved in cystine (C-C) bond formation

n

asparagine-linked (N-glycosidic) carbohydrates added to these residues, glycosylation patterns vary between some TSEs

s

(GPI) glycosyl phosphatidylinositol moiety attached (membrane anchor),

digesting this moiety gives

PrP^C its PI-PLC sensitivity and releases it from cells

mvlfssppvillisfliflivg

carboxy terminus removed before sending to cell surface

kkrpkpggwntggsrypgqgspggnryppqggggwgqphgggwgqphgggwgqphgggwg

qphgggwgqgggthsqwnkpskpktnmkhmagaaaagavvgglggymlgsamsrpiihfg

sdyedryyrenmhrypnqvyyrpmdeysnqnnfvhdcvnitikqhtvttttkgenftetd

vkmmervveqmcitqyeresqayyqrgs

the mature peptide found in 'normal' tissues
(amino acids 23-230)

Truncated forms of the human PrPr^Sc '27-30' found in amyloid plaques

gqphgggwgqphgggwgqphgggwgqphgggwgqgggthsqwnkpskpktnmkhmagaaa

agavvgglggymlgsamsrpiihfgsdyedryy

wgqphgggwgqgggthsqwnkpskpktnmkhmagaaaagavvgglggymlgsamsrpiih

fgsdyedryy

GSS (F198S) major peptides (58-150 and 81-150) found within amyloid plaques (mature-sized protein is found at the periphery of plaques)

wgqphgggwgqgggthsqwnkpskpktnmkhmagaaaagavvgglggymlgsamsrpiih

fgsdye

GSS (A117V & Q217R) major peptide (81-146) found within amyloid plaques

~gqgggthsqwnkpskpktnmkhmagaaaagavvgglggymlgsamsrpiihfgsdyedr

yyrenmhrypnqvyyr~

GSS (P102L) major peptide (~90~160) found within amyloid plaques

In short, a protease-resistant central core of the prion protein ranging in size from 27 to 30kDa is found in amyloid plaques of GSS patients and vCJD patients (although rare in BSE itself) and 75% of Kuru cases, but such amyloid plaques are only found in 5-10% of other CJD patients.

Note: the polypeptides found in amyloid plaques have loss their GPI anchor, glycosylation sites and structure-stabilizing cystine bond. At this point their tertiary structure is believed to be drastically different than that of the original protein.