Bmsc 220 8a Protein Sorting, Trafficking, and Secretion

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  1. events involving freshly made proteins
    -must fold into a distinct 3D conformation (1◦ aa sequence)

    -may associate with other polypeptide chains to be  assembled into a multi-subunit functional complex.

    -may have to be cleaved to be functionally active (insulin)

    -may undergo covalent modifications such as phosphorylation (and dephosphorylation), glycosylation, lipid addition

    -will eventually be tagged for degradation by the addition of small proteins such as ubiquitin

    -usually requires other proteins called chaperones (will discuss shortly) to help it achieve its final structure (chaperones are used even before translation is complete)
  2. Molecular chaperones
    • -proteins that facilitate the folding and translocation of other proteins
    • -DO NOT provide specific information on what the secondary or tertiary structure of a folded protein should be.
  3. Properties of chaperones
    • -Keeps protein unfolded until completely synthesized
    • - Keeps protein from incorrectly associating   with other proteins
    • - Bind hydrophobic aa’s
    • - Highly energy dependent
  4. two major branches ofprotein sorting
    cytosolic vs. secretory
  5. Cytosolic pathway
    -followed by proteins completed by Free cytosolic ribosomes

    • -nucleus
    • -mitochondria
    • -chloroplasts
    • -peroxisomes
  6. Secretory pathway for proteins
    -followed by proteins completed by membrane bound ribosomes(ER)

    • -Plasma membrane
    • -secretory vesicles
    • -endosomes
    • -lysosomes
    • -nuclear membrane proteins
    • -extracellular space
  7. Mitochondrial chaperones
    replace cytosolic chaperones when protein enters mitochondria (most compartments have their own chaperones)
  8. Why is secretory pathway a MISLEADING TERM:
    Not just for the secretion of proteins from cell, but carries out sorting of both free and membrane-bound proteins to some intracellular destinations
  9. chase
    period after radio labelling during which movement of the labeled proteins is observed
  10. The endoplasmic reticulum,
    • a network of membrane-enclosed tubules and sacs
    • -extends from the nuclear membrane throughout the cytoplasm.
  11. rough ER(RER) vs smooth ER (SER)
    rough is covered by ribosomes on its outer surface and is involved in protein metabolism.

    smooth is involved in lipid, rather than protein, metabolism and is not associated with ribosomes.
  12. C terminus (carboxyl terminus):
    end of peptide
  13. N terminus  (amino terminus):
    start of peptide
  14. •Signal recognition particles, (SRPs)
    -recognize and bind to signal sequences as the latter emerge from the ribosome on proteins being translated (the “address” of where the protein will go in coded for in the protein itself)

    -composed of small cytoplasmic non-coding RNA and proteins(another example of a ribonucleoprotein particle!)
  15. •SRP receptors
    proteins on the membrane of the endoplasmic reticulum that bind the signal recognition particle, SRP.
  16. A translocon
    a membrane channel (composed of SEC {secretory} proteins) through which polypeptide chains with a signal sequence are transported into the endoplasmic reticulum
  17. Cotranslational targeting of secretory proteins to the ER
    3 steps
    Step 1: Signal sequence on N terminus of growing protein binds SRP

    Step 2: SRP binds to SRP receptor on ER/ translocon

    Step 3: Ribosome sits over translocon channel and protein is synthesized into the channel

    Step 4: Signal peptidase enzyme on inner ER membrane/ translocon recognizes the signal sequence and cleaves it off the growing polypeptide chain (the protein is being synthesized “into” the translocon channel)

    Step 5: Complete protein (minus the SRP, which is not part of its 3D structure) enters ER lumen (unless there is a sequence in the protein that “locks” the protein into the ER membrane).
  18. BiP
    a molecular chaperone in the ER
  19. Two major classes of proteins targeted to the RER
    -Proteins destined for secretion from the cell or residence within the lumen of the ER, Golgi apparatus, endosomes, or lysosomes

    -Integral membrane proteins that are embedded by hydrophobic sequences spanning the phospholipid bilayer of membranes in the ER, Golgi, lysosomes, cell and plasma membrane
  20. the regions of polypeptide chains that are translocated into the ER lumen correspond to:
    domains of plasma membrane proteins that are exposed on the cell surface
  21. Why must Integral membrane proteins must be inserted in the correct orientation in the ER
    because these proteins cannot be “flipped” within the membrane and protein will stay in that orientation as it is moved from one membrane compartment to another
  22. The stop-transfer sequence
    1) stops the rest of the polypeptide from entering the lumen of the ER and

    2) changes the conformation of the translocon channel so that the channel opens, releasing the polypeptide chain to the ER membrane.
  23. How must Transmembrane proteins that will be incorporated into the plasma membrane travel to the plasma membrane?
    within a lipid bilayer
  24. How are new membrane lipids synthesized:
    in association with already existing cellular membranes of the smooth ER
  25. New phospholipids are added only to the ______-facing leaflet of the ER phospholipid bilayer membrane
  26. flippase
    • -flips phospholipids from one side of membrane to other
    • ex: from cytosolic leaflet to ER leaflet of ER
  27. The Golgi apparatus,or Golgi complex
    functions as a factory in which proteins received fromthe ER are further processed and sorted for transport to their eventualdestinations—endosomes, lysosomes, the plasma membrane, or secretion from the cell.
  28. Where is the cis vs. the trans face of the Golgi with respect to the nucleus?
    Cis face of Golgi =  closest to ER (where proteins enter)

    Trans face of Golgi =  furthest from ER(where proteins exit)
  29. How do proteins get to the Golgi apparatus from the ER
    1 vesicle budding

    2 Vesicle fusing with ERGIC

    3 Proteins move on to Golgi(cis face)
  30. Why do most (if not all) proteins destined for the ER travel to the Gogli and then back again to the ER?
    For sorting
  31. Where does the actual sorting of proteins therefore start?
    At the Golgi
  32. What is the role of ERGIC in the secretory pathway?
    Receive Vesicles of proteins from ER
  33. What are the two major steps that must correctly occur in order for proteins to be targeted to their correct cellular location?
    Step 1: correct protein to the correct vesicle(this vesicle has both membrane and luminal proteins – the “cargo” coming together in “pits”)

    Step 2: vesicle targeted to the correct intracellular location (or membrane)
  34. How to get the Correct protein to the right vesicle
    • -Protein processing within the Golgi involves the synthesis and/or extensive modification  of the carbohydrate portions of glycoproteins
    • -vesicles have specific receptor proteins for specific carbohydrates
  35. Vesicle protein coats
    protein coats that play a key role in ensuring the vesicles reach their correct targets within the cell following exit from the Golgi

    • ex
    • Clathrin, COPI, COPII
  36. Describe how mannose-6-phosphate residues target proteins to lysosomes.
    • -Golgi modifies lysosomal proteins to contain Mannose-6-phosphate residues
    • -Lysosomes contain receptor for mannose-6-phosphate .
  37. What are lysosomes?
    membrane-enclosed organelles that contain an array of enzymes capable of breaking down all types of biological polymers.
  38. What are coated vesicles?
    transport vesicles that carry secretory proteins from the ER to the Golgi and from the Golgi to other targets that are coated with cytosolic coat proteins
  39. What is clathrin?
    -a type of vesicle protein coats that sorts lysosomal proteins

    -attached to the receptor for mannose-6-phosphate
  40. acid hydrolases
    -active at the acidic pH that is maintained within lysosomes but not at the neutral pH characteristic of the rest of the cytoplasm.
  41. Why is it critical that lysosomal proteins are only targeted to lysosomes?
    -most of the enzymes destined for the lysosomes are only active in the acidic pH of lysosomes ; and therefore will not work that well in the more neutral pH of the cytoplasm; 

    - even though this is the case, you don’t want these enzymes even being minimally active or available in the cytoplasm because they will destroy almost everything in their path)
  42. What happens to lysosomal function in Tay-Sachs disease?
    -deficiency of beta-N-hexoamidase A, which   degrades ganglioside GM2 (major component   of brain cell membranes) due to autosomal recessive   mutation 

    -ganglioside accumulates in bloated lysosomes 

    -progressive decline in mental and motor functions beginning at age of 6 months, with death usually by age 4
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Bmsc 220 8a Protein Sorting, Trafficking, and Secretion
2013-10-19 04:48:52
Bmsc 220 8a Protein Sorting Trafficking Secretion

Bmsc 220 8a Protein Sorting, Trafficking, and Secretion
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