1-46 Correcting Protein Defects Flashcards
What is the protein-only hypothesis?
An explanation for the infective particle of TSEs. There are 2 covalently identical forms of prion protein (PrP):
- PrPC: non-pathogenic; soluble; protease-sensitive; 40% α-helix, a little β-sheet
- PrPSC: pathogenic; insoluble; protease-insensitive; 30% α-helix, 45% β-sheet
PrPC and PrPSC interconvert, with an equilibrium that favors PrPC. On very rare occasions when several PrPSC molecules come into contact, however, they can bind in β-sheets. These β-sheets can form stable, nucleus-like complexes that rapidly attract converted monomers and do not dissociate readily.
What do all proposed structural models of PrPSC have in common?
All proposed structural models of PrPSC contain a conversion to β-structure, followed by aggregation. Some models include:
- “β-helix” motif
- β-spiral
- Extended β-sheet
What are some potential therapies for TSEs?
The idea is to intervene at varous stages of amyloidosis.
- siRNA silencing of PrPC
- Stabilization of PrPC
- Immunotherapy (immunize using a PrP-PrP dimer)
- Disassembling amyloid fibrils with Hsp100-class chaperones
Increased levels of what peptide are associated with Alzheimer disease?
Aβ42.
When amyloid precursor protein (APP) is cleaved incorrectly, Aβ42 is produced instead of Aβ40. The amyloid fibers that make up Alzheimer plaques are virtually all Aβ42.
What is the amyloid cascade hypothesis?
The toxic species is not the mature amyloid fibril, but small, soluble aggregates of the misfolded peptide that form before the mature fibril. Aβ42 fibrils may simply be a by-product of disease or may even be protective (acting as a sink to soak up soluble oligomers).
What is the structure of the Aβ42 fibril?
A parallel, in-register β-sheet. Four copies of Aβ42 are shown. The fibril structure is stabilized by sidechain-sidechain interactions, mostly hydrophobic, between strands within the same peptide, as well as adjacent peptides.
What is Apolipoprotein E (ApoE)?
A lipid transport of 299 AAs with three isoforms: ApoE2, ApoE3, and ApoE4.
ApoE4 is associated with increased LDL (cardiovascular risk factor) and Aβ, and it is the strongest genetic risk factor for Alzheimer disease (found in 65-80% of patients).
How does ApoE4 differ from the other ApoE isoforms?
The arginines at positions 112 and 158. Arg112 can form an additional salt bridge with Glu109, which alters ApoE4’s substrate specificity relative to the other ApoE isoforms.
Disrupting this salt bridge with small molecules is a possible strategy for lowering the risk of Alzheimer disease.
What is islet amyloid polypeptide (IAPP, amylin)?
- A 37-residue peptide co-secreted w/ insulin by β-cells in islets of Langerhans. Incr. [IAPP] is assoc. w/ incr. insulin production.
- Structure: None in aq. solution, but it has helical tendencies and a hydrophobic face. Known to bind lipid bilayers (which may accelerate the rate of amyloid fibril assembly)
- IAPP amyloid is observed in ~90% of late-diabetes cases post-mortem
- Translating pig β-cells into humans may be effective at resotring insulin production
How do peptide inhibitors of Aβ and IAPP fibril formation work?
- All fibrils are β-sheets, which grow by forming sidechain-side chain interactions and peptide-peptide H-bonds
- Block (e.g., methylate) peptide nitrogens on the “growing” face of the β-strand so H-bonds cannot form to the next peptide
What is the pore hypothesis?
A plausible explanation for why amyloid fibrils appear to exert a neutral or even protective function in some diseases. Posits that soluble IAPP oligomers are more toxic than mature fibrils, and that pre-fibrillar species disrupt cell membranes.
- IAPP samples both α-helical and β-strand conformations, and in close proximity to each other
- α-helices associate to form a pore/other structure to disrupt the membrane
- β-strands can form a stable β-sheet, which “buds” off the cell membrane to generate higher-order oligomers
What is the receptor hypothesis?
A plausible explanation for why amyloid fibrils appear to exert a neutral or even protective function in some diseases. Posits that soluble IAPP oligomers are more toxic than mature fibrils.
- Soluble oligomers of Aβ42 bind to PrPC
- Aβ42/PrPC complex binds to and stimulates a glutamate receptor, which regulates several cellular pathways (incl. calcium signaling and protein translation)
- Monoclonal antibodies that inhibited the glutamate receptor resulted in reversal of physical and cognitive defects in mice
What is transthyretin (TTR) amyloidosis?
TTR is a tetramer of identical 127 AA subunits that binds and transports thyroxine, which stabilizes the tetramer and prevents it from dissociating to dimers/monomers. Disease-causing mutations at the thyroxine binding site can push equilibrium is toward TTR monomers, which can form amyloid fibrils that accumulate throughout the body and cause widespread organ failure.
