Regulation of Protein Degradation Flashcards
how does protein degradation and synthesis change in states of anabolism and catabolism?
synthesis exceeds degradation in anabolic states
vice versa for catabolic states
what are some reasons cells degrade their own proteins?
- removal of regulatory or rate limiting proteins
- quality control of mutated proteins (either mutated genetically or damaged by environment)
3 usage for energy (AA for gluconeogenesis)
4 angiten processing by the immune system
how are extracellular antigens and intracellular antigens degraded differently?
intra- ubiquitin
extra- endo-lysosomes
what are the 3 different ways to classify proteases?
active site nucleophile
-serine
-cysteine (lysosomal proteases)
-threonine (proteasome proteases)
- water (metalloproteases/acidic proteases)
these are the common residues found at active sites that enable them to act as enzymes
substrate specificity
- postively charged AA (trypsin)
- negatively charged AA
- hydrophobic AA
not every protease can cleave at every spot in the AA chain
cleavage location
- endoproteases- can cleave anywhere
- carboxypeptidase- can only cleave from carboxy end to amino
- aminopeptidase- can only cleave from amino end to carboxy
what are the different mechanisms that cells use to regulate protein degradation?
natural protease inhibitors (serpins)
inactive enzyme precursors (zymogens)
compartmentalization (lysosomes)
specific “death signals” (ubiquitin)
describe how lysosomes are formed
primary lysosomes are formed from the Golgi
secondary lysosomes formed via fusion with endosome or autophagosome
how are lysosomal proteases regulated?
compartmentalization
requirement for acidic conditions
specific protease inhibitors (cystatins)
what are lysosomal proteases called?
cathepsins
cathepsin K deficiency causes what?
disorder of bone developement- pyncodysostosis
dysfunctional osteoclasts
describe autophagy
non selective process of protein degradation activated by catabolic state
where are extracellular proteases required?
tissue remodeling complement cascade thrombin cascade- clotting plasmin cascade- fibrinolysis pancreatic proteases- digestion
serpins
natural serine protease inhibitors- inhibit proteases via irreversibly binding
serpin deficiencies
a-antitrypsin deficiency- unbalanced neutrophil elastase in lung causes emphysema
misfolded a-antitrypsin in liver causes aggregation
C1INH deficiency- C1 inhibitor of complement causes massive complement activation- anaphylaxis and swelling
antithrombin deficiency- thrombin causes clots. w/o removal, inapporpriate clotting
ubiquitin-protease pathway is selective
ok
describe ubiquitination
carboxyl group of ubiquitin activated using ATP by ubiquitin activating enzyme E1. Activated ubiquitin is then transferred to a ubiquitin carrier E2. E2 binds to E3 to form a ubiquitin ligase. ubiquitin ligase can then give ubiquitin to lysine residues forming an isopeptide bond
describe proteasome degradation
entry lid contains receptors that bind to ubiquitin tagged proteins, proteins to remove the ubiquitin (isopeptidases), and ATP dependent enzymes the unfold the substrate protein prior to entry into the cylindrical core (chaperones)
core contains multiple proteases w/ differing substrate specificities, which collectively degrade the protein. they only have threonine proteases
describe how the ubiquitin pathway is involved in cervical cancer
HPV encodes a viral ubiquitin ligase (E6) capable of degrading p53, which would stop cell division
instead cervical cancer forms
protein breakdown does not require energy. what does require energy?
preventing non-specific degradation
how does a proteasome inhibitor kill multiple myeloma?
multiple myeloma- cancer of plasma cells causing excess Ab. these cells are more sensitive to proteasome inhibitors and exclusively kill plasma cells
