1. Unfolded Protein Response
1.1. Sensors
1.1.1. IRE1
1.1.1.1. lumen side binds to misfolded protein
1.1.1.2. two IREs phosphorylate each other
1.1.1.3. activates RNAse activity of cytosolic domain
1.1.1.4. snips the introns out -> exon -> TR1
1.1.2. ATF6
1.1.2.1. lumen side binds to misfolded protein
1.1.2.2. vesicle forms carrying ATF6 to Golgi
1.1.2.3. Proteasome snips off cytosolic domain of ATF6
1.1.2.4. TR3 freed, turns on genes
1.1.3. PREP
1.1.3.1. lumen side binds to misfolded protein
1.1.3.2. two PREPs phosphorylate each other
1.1.3.3. activates kinase activity of PREP-> phosphorylates transcription initiation factor
1.1.3.4. phosphorylated TIF is inactivated -> less transcription
1.1.3.5. preferentially activates transcription of specific genes
1.2. ER
1.3. Effects
1.3.1. Decrease overall translation/transcription?
1.3.2. Increase production of chaperones
1.3.3. Ubiquitylate misfolded protiens
1.3.4. *if all else fails--APOPTOSIS
1.3.4.1. APOPTOSIS
2. Ubiquitin Proteasome Pathway
2.1. Used to destroy proteins
2.2. E1
2.2.1. Ubiquitin activating protein
2.2.2. Powered by ATP, transfers U to E2
2.3. E2
2.3.1. Ubiquitin conjugating protein
2.3.2. forms complex with E3 and substrate protein
2.3.3. transfers U to substrate
2.4. E3
2.4.1. Ubiquitin ligasing protein
2.4.2. complexes with substrate, this complex binds to E2 to transfer U to substrate
2.5. Form poly ubiquitin chain -> proteasome
2.5.1. Proteasome de ubiquitinates protein
2.5.2. Stretches out protein
2.5.3. Chops up protein into small fragments
3. Chaperones
3.1. Types
3.1.1. Multimeric
3.1.1.1. Protein enters, ATP causes conformational change, protein exits folded
3.1.1.2. aka chaperonins
3.1.1.3. e.g. HSP 60
3.1.2. Monomeric
3.1.2.1. Binds to specific domains to facilitate proper folding
3.1.2.2. ATP hydrolyzed into ADP, new ATP binding to the site causes release of protein
3.1.2.3. aka molecular chaperones
3.1.2.4. Most chaperones are monomeric
3.1.2.5. e.g. HSP 70
3.2. Can recognize
3.2.1. Misfolded proteins
3.2.2. Protein aggregates
3.2.3. Exposed hydrophobic regions
3.2.4. N-linked glycosylation