Prions

Teonanacatl eirik at ibm.net
Tue Apr 21 14:05:13 EST 1998


FRANK ROSCOE. wrote:
> 
> Seeking info on the structure of prions - especially related to CJD/BSE

This info might be a bit disorganised but I don't have time for more
now. Hope it helps, but if you want some more spesific info you can mail
me and I'll try to help........

The gene PRNP in humans codes for a relativly small protein called PrPc
(cause of CJD) (short for Prion Protein Cellular) consisting of 253
amino acid residues with a secondary structure consisting of about 42%
alpha-helices and almost no beta-sheet structure. This protein is
extensively post-translationally modified before it is embedded in the
membrane of different neurones where it serves some function not yet
understood in any significant detail although it is suspected to act as
some sort of receptor. The harmful version of this protein causing the
TSE’s is called PrPsc (short for Prion Protein Scrapie, from the
ruminant disease where it first appeared some 200-300 years ago). It is
this disease that probably at some point in time appeared as BSE after
cattle had been fed with food containing sheep brain and nervous tissue.
PrPsc is an isoform of the ‘normal’ PrPc protein and consists of about
54% beta-sheet, 25% alpha-helix, 10% turns & 11% random coils structure
and the difference is probably only conformational and does not involve
any changes in the proteins amino acid sequence. The change could also
involve covalent modification of an aa residue sidechain, a novel
cleavage or processing or differences in aggregation states. (by some
calculations it only takes about 10KJ/mol to change between the two
isoforms). Once the indegsted PrPsc is endocytosed or is synthesised
after a mutation in the PRNP gene it is believed to propagate with
direct interaction with a PrPc through an intermediate complex which
dissociates to release two new PrPsc particles which again interacts
with more PrPc and so on. The PrPsc is resistant to the normal cellular
degradation processes by proteosomes and aggregates in what is known as
prion rods and globular aggregates within the cell. It is uncertain
however if the disease is caused by the aggregation of PrPsc or by the
lack of PrPc’s normal function as they get transformed into PrPsc before
they can reach their usual position in the cell membrane. The
conformational changes is thought to take place within the
endosome-lysosome system and might be aided by some chaperons and
heat-shock proteins (HSP) which probably reside within that system just
on the inside of the cell membrane. The BSE prion is very similar in 3-D
space but has some significant differences in sequence.

PrPsc Human (sequence):
MANLGCWMLVLFVATWSDLGLCKKRPKPGGWNTGGSRRYPGQGSPGGNRYPPQGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQGGGTHSQWNKPSKPKTNMKHMAGAAAAGAVVGGLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYYRGSSMVLFSSPPVILLISFLIFLIVG

The following residues is identical in all the animals listed below:
7, 9, 11-13, 16, 18, 22-30, 31-50, 52, 54, 57-83, 92-93, 96, 98-99,
101-108, 110-111, 113-137, 140-142, 144, 146-154, 156-163, 165, 167,
169, 172-183, 185, 187-202, 204, 206-214, 216-218, 221-222, 224-226,
228, 231, 234-236, 238-245, 247-248, 250, 252-253

Gorilla
Chimpanzee
Mouse (*)
Rat
Syrian Hamster
Mink
Sheep
Goat
Cow
Greater Kudu

The mouse sequence corresponds to that of the NZW short incubation time
allele and differs from the long incubation allele at positions 109
(Leu/Phe) and 190 (Thr/Val) and because of the absence of residue 55 in
the NZWsi allele these are at 108 and 189. The cow allele used in this
sequence have six octapeptide repeats between residue 51-92 but bovine
PrPsc can have either six or five. There might of course be more alleles
for PrPsc.

Some info on hamster PrPsc (there hasn't been done any analysis like
this on human PrPsc):
aa residue 1-22 (a signal peptide) is removed during biosynthesis;
23-95, proline/glycine rich region contains 4 identical tandem
octapeptide repeats with 1 similar nonapeptide; 96-112, region
controlling topology of PrP called the Stop Transfer Effector; 112-135,
hydrophobic region, probably a transmembrane domain; 157-177, region
predicted to encode an amphiphatic helix; 232-254, hydrophobic signal
sequence removed on addition of the Glycosylated Phosphatidyl Inositol
(GPI) anchor at serine 231. Probable alpha-helices at 109-122, 129-141,
178-191, 202-218.



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