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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