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Protein Folding and Degradation

Topic updated on 09/20/17 10:28am

  • Overview
    • required for a protein to achieve a proper tertiary protein structure
    • involves heat shock proteins (Hsp)
      • essential for normal protein folding
      • some function as chaperones and some function as chaperonins
    • the more mutated a protein, the more help it needs from chaperones
    • if a protein is not folding properly, a chaperone may send it directly for degradation
    • clinical relevance
      • cystic fibrosis
        • pathogenesis
          • 3 nucleotide deletion on chromosome 7
          • ΔF508 mutation in chloride channel (CFTR) ↓ stability of the protein and ↑ folding time
          • instead of insertion into the plasma membrane the protein is degraded in the Golgi apparatus
          • ↓ chloride conductance results in ↓ Na+ and Cl reabsorption in sweat glands
        • presentation
          • ↓ water content of mucus which results in a thick mucus that cannot be cleared
            • respiratory infections
            • nasal polyps
            • malabsorption
            • meconium ileus
            • biliary cirrhosis
  • Chaperones
    • types
      • Hsp70
        • associates with directly with the ribosome
        • hides hydrophobic regions of protein to allow for proper folding
        • ATP hydrolysis required
        • essential
      • Hsp90
        • used for fewer proteins than Hsp70
        • ATP hydrolysis required
        • essential
        • role in folding mutant proteins in cancer
  • Chaperonins
    • group 1
      • Hsp60
        • ring shaped
        • ATP hydrolysis required
        • called GroEL/GroES in prokaryotes
        • peptide chain enters the cage and it is capped
        • once folded the cap is removed and the protein is released
    • group 2
      • TRiC/CCT
        • composed of 8 Hsp60s
        • similar function to GroEL/GroES
        • required for folding of actin and tubulin
  • Ubiquitination
    • cell's mechanism to mark a protein for destruction
    • mechanism
      • several copies of ubiquitin added to a misfolded/unneeded protein
      • polyubiquitinated protein enters the proteasome
      • protein hydrolyzed into peptide fragments
  • Defects in destruction of misfolded proteins
    • inability to send degraded proteins to proteasome results in accumulation in ER
    • examples
      • α1-antitrypsin (AAT) deficiency 
        • normally synthesized by hepatocytes and exocytosed into circulation
          • inhibit proteases
        • in AAT deficiency misfolded α1-antitrypsin accumulates in ER and damages hepatocytes 
          • PAS+ granules
        • many genetic variations
          • MC are Z and S variants due to point mutations
          • co-dominant allelic expression
        • presentation
          • micronodular cirrhosis
          • fibrosis
        • test with PCR


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