4 Protein Targeting

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  1. When the first 2 dozen AAs on the N-terminal of a newly synthesized protein have no particular signal:
    • protein completes translation in the cytoplasm by cytosolic ribosomes & will have 1 of 4 fates -

    • 1. cytosol
    • 2. mitochondria
    • 3. nucleus
    • 4. peroxisomes
  2. When the first 2 dozen AAs on the N-terminal of a newly synthesized protein are particularly hydropPHObic:
    • translation stops → moved to the ER → translation finished on the endoplasmic reticulum by RER ribosomes & will have 1 of 5 fates

    • 1. plasma membrane protein
    • 2. endoplasmic reticuclum
    • 3. secretory vesicles (be secreted)
    • 4. lysosomes
    • 5. golgi
  3. Signal Peptide/Sequence
    the first 2 dozen amino acids of a protein that specify which part of the cell the protein is going to

    the signal is located on a protein's N-terminus, or 5' end, that's synthesized first
  4. What is the targeting sequence for the Peroxisome?
    SKL (tri-peptide serene lysine leucine)

    • located on the C-terminus

    • a defect in SKL means the peroxisome won't have proteins to degrade toxins
  5. What targeting sequence means a protein belongs in the endoplasmic reticulum?
    KDEL (tetra peptide sequence)

    • used to retrieve proteins that try to escape from ER
  6. What is the targeting sequence for import into the nucleus?
    a short 5-7 basic amino acid sequence (small)
  7. What is the targeting sequence for import into the mitochondria?
    a LONG N-terminal AA sequence
  8. Chaperone Proteins
    • proteins that complex with nascent polypeptides & if they sense they're folded properly, direct them to their destination

    • are widely conserved from bacteria to humans

    • many are Heat-Shock Proteins (HSP)

    • conditions that cause unfolding of newly synthesized proteins (eg. elevated temperature, toxins) induce chaperone proteins

    • • they bind unfolded, mis-folded & aggregated proteins & CHAPERONE them to proteasomes for degradation
    • - are a major mechanism of getting rid of defective proteins

    • can be found in many cellular compartments (cytosol, Golgi, nucleus, mitochondria, ER, peroxisomes)
  9. Peroxisome
    organelles that break down oxidative products, detoxify cells, & contain enzymes that destroy free radicals
  10. What are the 2 diseases of defective peroxisomal targeting you need to know?
    1. Zellweger Syndrome

    2. NALD (Neonatal Adrenoleukodystrophy)
  11. What is the inside of the endoplasmic reticulum topologically equivalent to?
    the extracellular environment (the OUTSIDE of the cell)
  12. Golgi
    packages proteins inside the cell before they are sent to their destination

    • cis golgi is near the nucleus

    • trans golgi is farther from the nucleus (closer to the plasma membrane)

    Image Upload 1
  13. Where does translation of proteins occur?
    in the ER, but not in the Golgi
  14. Where does protein sorting, along with addition & trimming of sugars, occur?
    in the ER & Golgi
  15. Where does phosphorylation of lysosomal proteins occur?
    cis-Golgi ONLY
  16. Key Events in the ER & Golgi
    ER: translation, sorting, initial sugar addition

    cis Golgi network: Phosphorylation (+ trim, add, sort)

    cis, medial, & trans cisterna: trim, add, sort

    trans Golgi network: process & sort to either the lysosome, PM, or secretory vesicle
  17. Lysosome
    organelles with acid hydrolase enzymes that break down waste materials & cellular debris

    • degradative enzymes work best at low pH achieved by H+ ATPase pump in lysosome membrane (pH = 5)
  18. Lysosome Biogenesis
    • • let’s say you start with 2 proteins in the RER
    • • in the cis golgi network, mannose 6-phosphate kinase (a phosphotransferase) puts a phosphate group on the 6 position of a mannose residue on enzymes destined for the lysosome
    • • as the proteins move into the medial + trans golgi they physically separate
    • • the M6P receptor only recognizes mannose-6-phosphate groups
    • • other protein will be concentrated in the trans golgi → vesicle containing this protein will bud off → travel to the PM → fuse → release contents to ECM
    • • lysosomal protein + receptor has bud off in it’s own vesicle from the golgi & still exists at a neutral pH
    • • hydronium pump pumps in protons, lowering pH
    • • vesicle can now fuse with other highly acidic endosomes
    • • as the pH drops, the M6P receptor can no longer hold onto the lysosomal enzyme protein [even the phosphate group comes off]
    • • M6P receptors will physically separate & either be recycled to the trans golgi [to pick up more lysosomal enzymes] or will be shuttled to the plasma membrane [to pick up stray lysosomal membranes from neighboring cells]
    • • pure vesicle of lysosomal proteins will fuse with a lysosome
  19. What is the protein targeting sequence for the lysosome?

    • mannose 6-phosphate kinase adds phosphate to 6th position on a mannose sugar in a protein destined to be a lysosomal enzyme
  20. Fabry disease
    • caused by a defect in sphingolipid metabolism

    • was the 1st lysosomal storage disease successfully treated with enzyme replacement therapy
  21. Gaucher disease
    • caused by a defect in sphingolipid metabolism

    • successfully treated with enzyme replacement therapy
  22. Tay-Sachs
    • caused by a defect in sphingolipid metabolism

    • prevalent in Ashkenazi Jews (common on East Coast)
  23. MuCoPolySaccharidoses [MCPS]
    • caused by a defect in 1 of the several enzymes needed to break down Glycosaminoglycans

    • a few can be treated with enzyme replacement or enzyme enhancement therapies

    eg. Hunter, Hurler, Sanfillipo, Pompe, Morquio
  24. I-Cell Diseases (Inclusion-cell)
    • • proteins are not properly targeted for lysosome in the Golgi
    • • M6P signal is missing
    • • end up being secreted → build up of substances in lysosomes because there's no enzyme to degrade them
    • • caused by a defect in the phosphotransferase that puts a phosphate group on the 6-position of specific mannose residues
    • • can also be caused by a defective mannose-6-phosphate receptor protein (rare)
    • • no lysosomal enzymes get to lysosomes → all substrates constipate the lysosome
    • • rare disease that revealed mechanisms for LSD & lysosomal/organellar biogenesis
  25. What are 3 diseases that can be treated with enzyme replacement therapy?
    • 1. Fabry's
    • 2. Goucher's
    • 3. [Hunter’s, a MCPS]
  26. [Huntington Disease]
    another protein targeting disease: cytoplasmic proteins accumulate in nucleus because of mutation that creates NLS signal
Card Set:
4 Protein Targeting
2016-08-27 22:41:12
MedFoundationsI CellBiology Exam1
Cell Biology Exam 1
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