Lecture #07: Protein Misfolding & Disease/Hemoglobin Flashcards
Denaturation
• Denaturation is when protein is completely unfolded. Loss of secondary and higher order structure. Noncovalent interactions are disrupted, but peptide bonds remain intact. Results ultimately in loss of activity.
Misfolding
• Misfolding is when protein retains structure, but the way it is folded is not correct. Can result in loss of activity. What usually happens to these proteins is that they’re refolded, degraded, or form aggregates/amyloid fibers and cause a disease
Chaperonins
• Chaperonins, a group of proteins, are responsible for refolding misfolded proteins. First called heat-shock proteins because if you heat shocked something, there was an increase in production of these proteins. Makes sense because heat is a denaturing agent.
○ Basically a quality control mechanism to help the cell survive any incidents of protein misfolding.
○ Use ATP to accelerate the folding process. Going to make the protein as stable as it possibly can be.
Heat Shock vs. Lethal Heat Shock
○ A heat shock is going up from usual temperature 37 degrees of protein environment to 42 degrees celsius. Or 44 degrees, which is a lethal heat shock. If proteins experience heat shock for too long, chaperonins can’t do anything.
Proteasomes
• Proteasomes also deal with protein misfolding. Made up of a number of proteins that work together to completely degrade a misfolded protein to recycle all the amino acids. Can be reused in new proteins.
Defective Chaperonins and Proteasomes
• If proteasomes or chaperonins are defective, then you have tendency to develop aggregated proteins. They stick together, become insoluble, and form fibers.
Unfolding Affects on Hydrophobic Residues
• When you unfold protein, you’ll expose hydrophobic regions. Now that they’re forced to act with water, they’ll instead interact with one another. They stick together and become to attract other hydrophobic residues, forming an aggregate.
Amyloid
• Another way to develop these aggregates has something to do with amyloid segments. They’re short sequences, not all hydrophobic, which are normally present in the interior of the protein. So if they’re exposed to water, they form the sticky aggregate and form an amyloid, because they’re becoming sticky to one another.
○ Any protein that can form fibers and become insoluble and resistant to degradation is labeled amyloid.
Sickle Cell Anemia
• In Sickle Cell Anemia, valine is going to replace glutamic acid. This group is facing outward, and valine is hydrophobic. So what happens because you have a hydrophobic side chain facing the water. So this is going to result in aggregation of Hb molecules and formation of insoluble fibers that result in the sickle shape. These fibers are considered amyloid.
Amyloid Formation
• When an amyloid is forming, they form a highly ordered beta-sheet. One of characteristics of amyloid is that the alpha-helical regions of protein now become beta-sheets. So a protein that is already a beta-sheet will not necessarily form a amyloid. Only when you do this conformational switch is when you form these long fibers, become resistant to degradation due to aggregating upon one another.
Amyloid Associated Diseases
• Amyloid Associated Diseases include Alzheimer’s, Parkinson’s, AML (Lou Gehrig’s Disease). Proteins are converted from normally soluble forms to insoluble fibrils which accumulate.
Prion Protein: Diseases
• Prion Protein is a particularly important protein. Found in brain, it is associated with mad cow disease and Creutzfeldt-Jakob disease (inherited point mutation).
Prion Protein Infectious
○ It was called infectious. But how can a protein be infectious? The normal conformation of it is primarily alpha-helical. The diseased conformation transforms some of the alpha-helical structures into beta-sheets. Prion is infectious because they can form aggregates and fibers. When they interact with a NORMAL conformation of the prion, the normal prion becomes the diseased prion.
§ It does not cause other proteins to misfold, but only a fellow prion.
Prion Protein Anchor
○ The way the protein is anchored in the plasma membrane is by a modified phospholipid. Only thing holding protein in membrane. Only held in membrane by short anchor, and most of it is facing outside the cell.
Neurodegenerative Diseases
• Neurodegenerative diseases are not necessarily infectious, but these particular aggregated amyloid fibers can be transferred from one cell to the next. And this is how the disease, like Alzheimer’s, progresses. It does not transfer from human to human, but cell to cell.
