1. _______ is continuous with the rough ER
    Outer nuclear membrane
  2. Secreted and membrane biosynthesis is a function of (rough/smooth/both)
  3. Phospholipid and cholesterol synthesis is a function of (rough/smooth/both)
  4. Calcium storage is a function of (rough/smooth/both)
    Both (but especially in sarcoplasmic reticulum in muscle cells, which is part of smooth ER)
  5. MHC Class-I antigen presentation is a function of (rough/smooth/both)
  6. Steroid synthesis is a function of (rough/smooth/both)
  7. Oxidative modification of xenobiotics (p450) is a function of (rough/smooth/both)
  8. Glucuronidation of bilirubin and other compounds in the liver is a function of (rough/smooth/both)
  9. COPII vesicle formation is a function of (rough/smooth/both)
  10. ER client proteins and non-ER client proteins
    • Clients:
    • Secreted proteins (peptide hormones, extracellular enzymes, immunoglobulins, ECM proteins)
    • Integral membrane proteins of endomembrane system (e.g. receptors, transporters and channels, cell adhesion proteins)
    • Lumenal proteins of the endomembrane system (e.g. lysosomal hydrolyses, ER chaperones)
    • Non-clients:
    • Cytosolic proteins (e.g. cytoskeletal, contractile, soluble enzymes)
    • Peripheral membrane proteins on cytoplasmic face (e.g. spectrin)
    • Nuclear, mitochondrial, and most peroxisomal proteins
  11. SRP
    • Signal Recognition Particle
    • Binds to signal sequence of nascent polypeptide as it emerges from the ribosome to signal translocation into the ER lumen
  12. SRP receptor
    Located in ER membrane; binds SRP/ribosome complex to start translocation of polypeptide into ER lumen
  13. Translocation of water soluble proteins
    • As new polypeptide is being synthesized, it contains a signal sequence
    • SRP, or signal recognition particle, binds to signal sequence
    • SRP receptor binds SRP/ribosome complex SRP is released, passing ribosome to a protein translocation channel in the ER membrane. Thus, the SRP and SRP receptor are “molecular matchmakers”
    • Signal sequence also functions to open the protein translocation channel (Sec61 complex). It remains bound to the protein translocation channel as the rest of the translating polypeptide is threaded into the ER lumen in a large loop
    • Once the protein is threaded into the ER lumen, a signal peptidase (located on the luminal side of the ER membrane) cleaves the rest of the polypeptide from the signal sequence, and the signal sequence is rapidly degraded (with the new polypeptide in the ER lumen)
  14. Translocation of transmembrane proteins
    • N-terminal signal sequence, or sometimes internal signal sequence consisting of hydrophobic amino acids, signals translocation (just like for water soluble proteins)
    • Polypeptide is threaded through protein translocation channel until it reaches a stop signal sequence, which consists of hydrophobic amino acids
    • Signal peptidase cleaves polypeptide, and the stop signal sequence is released laterally and becomes the transmembrane segment of the new polypeptide
    • For multipass transmembrane proteins, more pairs of internal signal sequences and stop signal sequences
  15. Sec61 Complex
    Translocation pore located in the ER membrane
  16. N-linked glycosylation
    Addition of polysaccharide to the amide group of an asparagine residue to form a glycoprotein
  17. Formation of disulfide bonds happens on (cytoplasmic/luminal) side of ER membrane. Why?
    • Luminal
    • Luminal side is an oxidative environment; cytosol is reducing environment, so it cannot happen there
  18. Chaperones
    facilitate folding and oxidation of polypeptides in the ER lumen
  19. BiP
    • Binding immunoglobulin protein
    • ATPase
    • An example of a chaperone protein; binds to hydrophobic amino acid sequences and prevents aggregation and facilitates protein folding
  20. Calnexin-Calreticulin
    • Chaperones with lectin properties that bind to glucose on glycoproteins, promoting protein folding
    • Loss of glucose residues releases protein from calnexin-calreticulin
  21. Where does protein subunit formation occur?
  22. ERAD
    • ER Associated Degradation
    • Mechanism to degrade misfolded or slowly folding proteins
    • Misfolded proteins remain in the ER lumen due to their association with chaperones
    • Ubiquitin ligase attaches a ubiquitin to lysine groups on the proteins, signaling the protein to be sent to the proteasome for degradation
    • Ubiquitin is recycled and reused
  23. Ubiquitin
    Small protein that is covalently attached to lysine groups on a misfolded protein, signaling degradation of the misfolded protein
  24. Ubiquitin ligase
    Attaches ubiquitin to misfolded protein
  25. Proteasome
    Protein complex that degrades misfolded proteins
  26. delF508 mutation in CFTR
    • Cystic Fibrosis Transmembrane Regulator
    • Causes misfolding of CFTR channel, leading it to be degraded by ERAD
  27. ______ buffer the toxic effects of misfolded/unfolded proteins
  28. ER Stress
    • An imbalance between the capacity of the ER to process client proteins and the load of client proteins imposed on the organelle
    • There are molecules that mediate the response to ER stress (ATF6, IRE1, PERK); these molecules enhance gene expression of ER components to increase the capacity of the ER, while also reducing translation of the toxic proteins that contribute to the stress
  29. Autophagy
    • Method of ridding cell of malfolded proteins accumulating in the ER; alternate to ERAD
    • ER-derived membrane known as a phagophore engulfs swath of cytoplasm and its associated organelles, forming an autophagosome
    • The autophagosome fuses with a lysosome, forming an autophagolysosome
    • Degradation occurs
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