prion Flashcards
NONINFECTIOUS PRION
detail. PrP is a host-encoded protein which
exists as PrPC (cellular) in the non-infected host,
infectious prion
PrPSc (scrapie) as the major
component of the scrapie infectious agent
hoy infectious prion are different from non infectious
biophysical features of PrPSc
are drastically different in respect to solubility, structure, and stability;
furthermore, specific lipids and a polyglucose scaffold were found in prions,
whereas for nucleic acids their absence could be proven.
infection stage of prion
highly enigmatic properties of
the infectious agent were demonstrated, such as absence of particles in the
electron microscope, no immune response during the infection, and high
resistance of the agent against chemical and physical treatment
PrP is always isolated as
a mixture of three forms –
unglycosylated, with one glycosyl-, and with two glycosyl-groups. A
disulphide bridge is formed between Cys179 and Cys214. As indicated
in Plate I, PrP contains 2 hexarepeats and 5 octarepeats in its N-terminus
(see Prusiner7 and Weissmann8
The lipophilic nature of highly purified prions suggested
a glycolipid anchor is linked to PrP but, in addition, lipids might be
associated non-covalently with PrP
type of lipid in prion
lipids which amounted to around 1% of purified prions19. These are
sphingomyelin, α-hydroxy-cerebroside and cholesterol depending on the
method of purification. Both lipids are known to be components of the
outside of the cell membrane in caveolae-like sites, where PrPC also
accumulates. It could not be shown that the lipids are essential for
infectivity, but their presence in prions might indicate the origin of
prions, namely the site of PrPC accumulation on the outside of the cell
membrane.
differnece between two prion
PrPC and PrPSc are different in respect
to solubility, fibril formation, proteinase K resistance and other features.
how they diffrent sturcturally
The glycosyl-groups of PrPC probably
do not alter the structure significantly, but the fact that PrPC is attached
to the membrane by the glycolipid anchor might have more influence,
particularly if one considers the structure of the N-terminus which was
found unstructured when free in solution (see above). Furthermore, it is
known that the N-terminus and, in particular, the octarepeat of the Nterminus
bind 4–6 copper ions in a co-operative manner which definitely
would induce more structure than presently known from the NMR
analysis
The NMR-structure of PrP is
a monomeric structure. Several reports
in the literature indicate that PrP in its α-helical structure can form
dimers under physiological or close to physiological conditions29,30.
Dimers in solution show the intact intramolecular disulphide bridge.
Consequently, dimerization is not induced by oxidizing the disulphide
bridge and reforming it in an intermolecular structure
prion state
the thermodynamically stable state is the PrPSc-like state, and
this would be true for lysosomal acidic pH or the cell-surface neutral
pH
conclusion
weeks). Formation of the β-sheet-rich structure is always
correlated with oligomerization at least if the naturally occurring
disulphide bridge is intact. Whether β-sheet oligomers are intermediates
on the pathway to PrPSc or a dead-end product is at present an artificial
discussion because the PrPSc-like state as available is not infectious and
a final decision on the right pathway cannot be made. If the PrPCconformation
is not the thermodynamically stable state, but only
metastable, the question remains why a transition to PrPSc does not
occur much more frequently in nature as a spontaneous transition. It is,
however, not a discrepancy if one takes into account that PrPC is
anchored in the lipid membrane, and all studies described were carried
out in aqueous buffer. Consequently, as an additional transition of PrPC,
one has to include the distribution between the aqueous and the lipid
phase which would definitely stabilize PrPC in nature to prevent a
spontaneous transition.
