Biochem Lectures 39&40 (Protein Degradation)

Question 1

What are the major pathways of protein degradation?

Answer 1

1. lysosomal
2. ubiquination-proteasomal
3. extracellular proteases

Question 2

Why would a cell want to degrade proteins?

Answer 2

1. quality control—get rid of bad prots
2. controlling metabolsim—break down prots involved in rate-limiting steps (e.g. degrading cyclins allows mitosis to procede)
3. antigen presentation
4. energy source (esp in catabolic states; autophagy)

Question 3

How do you get a misfolded protein?

Answer 3

DNA encoding for it has mutation

error in synthesis (>30% of mRNAs have error in them)

damage (e.g. from ROSs or UV light)

Question 4

What are Mallory bodies?

Answer 4

large protein depos in liver; common in EtOH abuse; cannot be degraded, build-up and cause problems

Question 5

Match the follow:

MHC-I vs. MHC II

with

CD4 vs. CD8

and

endosome-lysosome vs. ubiq-proteasome

Answer 5

extracellular Ag—>endo/lysosome—>MHC II—>CD4

intracell. Ag—>ubiq-proteasome—>MHC-I—>CD8

Question 6

If protein degradation is exergonic, why is ATP needed?

Answer 6

ATP used in regulation to prevent uncontrolled prot degrad

Question 7

In what ways is protein degradation regulated?

Answer 7

1. natural protease inhibitors (e.g. Serpins)
2. zymogens (inactive enzyme precursors)
3. compartmentalization
4. ubiquination (other “Death” signals?)

Question 8

What enzymes work in lysosomal degradation? how are they regulated?

Answer 8

cathepsins

regulated by:

1) compartmentalized into lyososome
2) only work in the low pH of the lysosome so even if they get out they won’t do much damage
* low pH is due to ATP-dep proton pump (example of why protein degradation requires ATP)*
3) if they get out, not only will the pH be a problem, cystatins in the cytosol

Question 9

What are some examples of physiological processes that require extracellular proteases?

Answer 9

• complement cascade
• clotting cascade
• fibrinolysis
• digestive enzyme activation
• tissue remodeling

Question 10

Describe the ubiquination mechanism

Answer 10

ubiq is attached to target prot via a isopeptide bond: bond is not made to N- or C- terminals but rather to middle of peptide at a Lysine residues

*isopeptide bonds were discovered along with this ubiq-prot mechanism

Question 11

What are the steps involved in the proteasome’s mechanism?

Answer 11

1) Target protein is recognized by poly-ubiq recog in lid
2) must be “linearized” (using ATP and chaperones), and then de-ubiquinated (isopeptidase)
3) passes through body of proteasome with inward-facing Thr-proteases