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Updated: Jun 6 2021

Protein Folding and Degradation

  • Folding
    • 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
  • Degradation
    • 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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