Regulation of Protein Degradation Flashcards
three pathways of protein degradation
(1) lysosomes
(2) extracellular proteases
(3) ubiquitin-proteasome pathway
How do cells regulate protein degradation?
- natural protease inhibitors (e.g. serpins)
- inactive enzyme precursors (e.g. lysosomes)
- compartmentalization (e.g. lysosome)
- specific “death signals” (e.g. ubiquitin)
regulation of lysosomal proteases (cathepsins)
- compartmentalization
- req for acidic conditions, provided by lysosomal proton pump
- cystatins = specific cathepsin inhibitors
cystatins
specific cathepsin inhibitors involved in regulating lysosomal proteases/cathepsins
cathepsin K deficiency causes _____
genetic disorder of bone development - ex. pycnodysostosis
serpin
serine protease inhibitor
genetic diseases caused by deficiencies of specific serpins
- alpha1-antitrypsin deficiency
- C1INH deficiency
- antibthrombin deficiency
cystic fibrosis
mutated chloride channel protein is functional, but rapidly degraded
pycnodysostosis
ex. problem w/ lysosome pathway of protein degradation
rare lysosomal storage disease; cathepsin K deficiency –> dysfunctional osteoclast
emphysema and liver failure in 30 yo smoker
ex. problem w/ extracellular protease pathway of protein degradation
neutrophils in lung, protein deposits in liver
alpha1-antitrypsin deficiency
ex. problem w/ extracellular protease pathway of protein degradation
- common genetic disease affecting 1/1000 northern europeans
- unbalanced neutrophil elastase activity in lung –> emphysema
- misfolded alpha1-antitrypsin protein in liver –> aggregation
C1INH deficiency
ex. problem w/ extracellular protease pathway of protein degradation
- symptoms: recurrent tongue swelling and shortness of breath
- lack of C1 inhibitor causes massive complement activation –> angioedema (anaphylaxis and airway swelling)
antithrombin deficiency
ex. problem w/ extracellular protease pathway of protein degradation
- unregulated clotting events throughout body
- worse during pregnancy
isopeptide bond
important in ubiquitin pathway: the initial bond formed b/t ubiquitin and the target protein
entry lid of proteasome contains:
receptor proteins that bind to ubiquitin-tagged proteins, de-ubiquitinating enzymes, ATP-dependent enzymes for unfolding
