Proteinopathies Flashcards
non-covantent interactions that dictate and stabilize protein structures
electrostatic interactions, h-bonding, dipole, hydrophobic interactions
role of chaperones
prevent protein misfiling by helping proteins overcome kinetic energy barriers to forming native state/avoid getting stuck in local minima
Why do incompletely folded proteins form aggregates?
they have hydrophobic residues on their surface and can easily associate with one another
chaperonins
large, cylindrical complexes that have a central compartment for a single protein chain to fold without possibility of aggregation
Molecular basis of Alzheimer’s disease
extracellular amyloid-B (AB) deposits and intracellular neurofibrillary tangles of tau proteins - triggered by phosphorylation of tau in neurons by AB
amyloid-B (AB)
proteolytic fragments of amyloid precursor protein (APP) formed by cleavage of APP by B-secretase followed by y-secretase.
toxic as small oligomers, less toxic as long fibrils visible as plaques
differences between hyperphosphorylated and normal tau protein
normal tau is soluble and promotes assembly of microtubules
hyperphosphorylated tau is insoluble, does not have affinity for microtubules, and aggregates into paired helical filament structures.
mutations responsible for familial AD
overproduction of AB due to mutations the genes for APP or y-secretase
Why do adults with Down syndrome have higher rates of early-onset AD?
APP is on chromosome 21 - Down syndrome = extra chromosome 21 = increased expression of APP
APOE genotypes and risk
ApoE4 has Arg at both positions (112, 158) and increases risk for AD (more so for individuals with E4/E4 than E3/E4, E2/E4).
ApoE3 is the neutral ApoE genotype
Molecular basis of Parkinson’s disease
accumulation of neurofibrillary tangles made of polymers of a-synuclein protein, which is in neural tissue at the presynaptic terminals.
called levy bodies
a-synuclein known to interact with tau, and also forms amyloid filaments
molecular basis of Huntington’s disease
CAG repeat expansion for polyglutamine sequences near Huntington protein.
amyloid-like fibrils that contain B-sheet structures, with small aggregates being more toxic
Huntingtons disease and genetic likelihood of developing it
autosomal dominant
HTT gene with fewer than 35 CAG repeats do not develop disease.
HTT gene with 40+ CAG repeats develop disease as they age.
longer repeats = increased severity and earlier onset
exhibits anticipation
prions
proteins acting as infectious agents without DNA/RNA, which cause transmissible spongiform encephalopathies - neurogenerative disorders
molecular basis of prion diseases
deposits of insoluble, protease-resistant PrP that aggregate into fibrils - mostly organized into B-sheets rather than a-helices of normal PrP protein
genetic mutations that are associated with inherited prions disease & somatic prion disease are located on which gene?
PRNP - which encodes for prion protein
How is Creutzfeldt-Jakob disease transmitted?
inherited, sporadic, infectious, or iatrogenic (from corneal transplants, surgical instruments, formerly from growth hormone derived from cadavers)
How can prions that cause Creutzfeldt-Jakob disease be removed from surgical instruments?
sterilize with alkali rather than heat
Genetic mutations associated with Parkinsons disease
Parkin, UCHL1 - involved in ubiquitin degradation of misfiled proteins.
SNCA - gene coding for a-synuclein - cause misfiling or over-expression of a-synuclein
what is the most important driver of protein folding?
hydrophobic effect - folding a protein so that the hydrophobic sidechains are clustered together in the interior decreases the number of water molecules in contact with the hydrocarbon and results in a net increase in the entropy of the water - decrease in total free energy
Why are prion proteins resistant to proteases, heat, and detergent?
misfiled PrP protein is highly stablehand resistant to protein unfolding. heat and detergent cannot unfold them, and proteases cannot access the peptide bonds to cleave them due to PrP protein’s rigidity
What is the only way to destroy a prion?
alter chemical structure by hydrolyzing peptide bonds with a strong base or oxidizing its functional groups with a strong oxidant
How would a reduced expression of chaperones increase the risk of AD?
chaperones interact with misfiled proteins until they refold or are degraded - because AB is difficult to refold or degrade, chaperones get tied up with them and if there are fewer chaperones to begin with, AB would be allowed to accumulate.
