protein misfolding and disease Flashcards
1
Q
protein degradation in proteosomes
A
E1 activates ubiquitin
E2 carries ubiquitin to target
E3 binds to llysine on target
-ATPase subunit unfolds, protein threaded through and cleaved into small peptides
2
Q
Mechanisms for misfolded proteins to cause disease
A
- loss of function
2, alternate conformation - gain function
3
Q
How mutations make proteins defective
A
- point mutation/direct knockout
- destablize
- loss of function/gain of toxic function
4
Q
p53 point mutation causing disease
A
- a tumor suppressor stimulated by DNA damage
- p53 is a tetramer mostly of B sheets but binding site for DNA are alpha helices and loops
- a DNA contact mutation is when binding site is altered but not the rest of the structure
- stability mutation is when protein destabilizes bc bonds are disrupted. can cause accumulation of mutant p53
- in most cells destabilization causes increased degradation
- therapy for destabilizing mutation would be to bring in small mlc (Zn) to stabilize
- MDM2 is an E3 ligase that binds p53 for ubiquitination. block MDM2 to increase p53 activity
- no current treatments for a direct knockout mutation
5
Q
Cystic fibrosis described by proteins
A
- a destabilization/altered folding due to removal of surface residue
- folding stops as intermediate
- treat by stabilizing, using chaperones, inhibiting proteasomes, opening Cl- channel
6
Q
serpins
A
- a1AT deficiency causes lung and liver disease
- a1AT is a serpin– serine protease inhibitor - inhibits polypeptide cleavage
- a1AT inhibits neutrophil elastase. need this to prevent too much breakdown of connective tissue
- loss of function, gain of toxic function
- normally, neutrophil elastase inserts into B sheets of a1AT and breaks bonds of a1AT- this inhibits neutrophil elastase (mouse trap)
- problem if the neutrophil eslastase can bind to neighbors too. get runaway polymerization and accumulation in liver.
- block polymerization by inserting short peptides into B sheets
