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Prion Diseases: Mechanism of Prion Propagation (INHERITED DISEASES (only…
Prion Diseases: Mechanism of Prion Propagation
INFECTIOUS DISEASES
misfolded & cellular forms of PrP have affinity due to identical primary sequence
hydrophobic residues on surface of PrP-Sc induce globular PrP-C to misfold into form rich in Beta sheets
Infection @ molecular structural level b/c PrP-Sc has essentially entered system and copied system
Each misfolded prion protein acts as "seed" or template causing/to nucleate further misfolding
Result:
prion amyloids
= plaques of stacked fibrous PrP-Sc
INHERITED DISEASES
only 5% of CJD cases
85% from random mutations rather than mutations from parents
primary sequence mutations destabilizes alpha helical structure of PrP-C
protein encouraged to misfold into form rich in Beta sheets b/c relatively more stable
First misfolded PrP-Sc goes on to induce more misfoldings -> plaques build up in the brain
BUT initial mutation makes it harder for first PrP-Sc to have affinity w/ cellular forms
However this doesn't stop it from inducing misfolding in at least one other protein, which then triggers faster propagation
~30 PRNP gene mutations linked to inherited prion disease, including point mutations, insertions, stop codons
diff. mutations can lead to same disease
Octarepeat inserts don't cause disease, but make you more susceptible to developing certain diseases
loss of H-bonding and salt bridges in unstructured 1st half of protein doesn't have major destabilization effects, instead lowers activation energy required to misfold
BUT mutations are rather adding bulk side chains -> favoring more stable Beta sheet form to replace the alpha helices
mutations in structured 2nd half of protein may actually destabilize the alpha helices, increasing free energy and making misfolding easier
GROWTH OF FIBERS
hydrophobic residues exposed on end of fiber
thus newly made monomeric PrP-Sc is recruited to elongate the fiber
these induce the misfolding of nearby PrP-C
Graphed with fibril fluorescence (y) plotted against time (x)
Starting
lag phase
= kinetic barrier to forming fibers
After initial seed induces a few other misfoldings, fibril formation occurs exponentially ->
elongation phase
when fiber gets more and more stable
process occurs in minutes (shaken, high-conc. test tube) to a week (non shaken, low conc.)
PRION PROPAGATION 2 Models
Autocatalytic Nucleated Polymerization
PrP-C attracted to PrP-Sc seed
PrP-C's location adjacent to seed induces/catalyses misfolding
thus new PrP-Sc unit added to fiber
Non-catalytic Nucleated Polymerization
PrP-C molecules naturally undergo rapid conformational changes b/w native form and hybrid/unfolded form
Hybrid/unfolded form interacts with seed -> further misfolds to PrP-Sc shape
thus new PrP-Sc unit added to fiber
STRAINS OF PRION DISEASE
diffs explained as diffs in structure of misfolded aggregates (fiber morphology)
these diffs hypothesized to result from slightly diff environmental conditions that impact how fibers stack
strains differ w/ locations of protein aggregates
different fiber structural properties influences disease pathology
strains also differ @ molecular level
evident from unique protease fragmentation run on Western blot
makes sense b/c prion protein is folded slightly differently in each strain, leaving diff. .regions protected vs. exposed to digestion enzymes
Species Barrier
Intraspecies
Transmission: easy infection
Interspecies
Transmission: longer incubation period before full infection
believed to be caused by diffs in primary sequence b/w mammals
nucleation of misfolding is slower or doesn't happen b/w PrP-Sc and PrP-C w/ diff primary sequences
Parent-Daughter Seeding
Morphology of parent seed dictates morphology of daughter fiber
adding one form of fiber to soluble monomers will seed the same structure of fiber, even if conditions are diff. from those that created the original seed itself
Template Assisted Conformational Switch