1-46 Protein Misfolding and Disease

Question 1

what markes the protein for degredation?

Answer 1

a 4 unit polyubiquitin chain

Question 2

after the protein is marked for degredation

Answer 2

it is taken to the 100hsp proteosome. Caping protein (AAA) recongizes protein. brings it into the cavity where it is cleaved into small peices and recycled (if self) or cut into larger fragments (if non self) to be used as antigen presentation by MCH class 1

Question 3

protein degredation is key in many ________

Answer 3

cellular processes. so when it goes awry, it can cause many diseases such as cancer, neurodegeretive dsorders, CF, and autoimmune diseases

Question 4

three main mechanisms by which defective proteins cause disease

Answer 4

loss of protein function, protein malformation (toxic folds), and gain of protein function

Question 5

three main ways that loss of protein function may occur and example

Answer 5

1. direct knockout - mutation of residue that is essentail for function, such as in the active site of an enzyme
2. destabalization - mutation pushes equilibrium to towards unfolded state.
3. toxic conformation - mutation pushes conformation equilibrium not towards unfolded state, but incorrectly folded state that can cause aggregation

Question 6

p53

Answer 6

the trainscription factor that coordinates the DDR and leads to cell death when genome has been thoroughly damaged

Question 7

mutation of p53 is found in most

Answer 7

cancers

Question 8

Three ways that p53 can be mutated

Answer 8

hampered DNA contact - certain residues in DNA binding domain knocked out, cannot fit on and interact with DNA

destablization - certain residues outside of DNA binding domain are altered/knocked out - the p53 can be forced to unfold

lowered zinc binding affinity - certain residues NEAR the dna binding site altered/knocked out, p53 will not have as high a zinc binding affinity. Zinc stabalizes the loop motif that protrudes into the DNA moleucle - without it, the loop is not functional

Question 9

serpins

example? 2 types of mutation

Answer 9

serine protease inhibitors.

ex) alpha-1-antitrypsin
Z type = glu to lys, s type = glu to val
both lead to loss of lung connective tissue and cancer/cirrhosis of liver

Question 10

why does lung damage happen when a-1-a is mutated?

liver?

Answer 10

neutrophil elastase enzymes secreted at sites of inlfmamation. if not cleared out by a1a, extensive digestion of connective tissue by elastases occurs.

-when they reach the liver, they do not get cleared, leading to accumulation

Question 11

CFTR

what causes 70% of CF cases?

Answer 11

member of family of proteins called ATP binding casette trasnporters, pump solutes into and out of the cell

deletion of Phe residue in CFTR is the cause of 70% CF. causes a loss of nucleotide binding domain (NBD1)and membrane spanning domain (MSD1) interaction, causing protein folding to arrest. ER quality control system tags protein for degradation by proteosome.

Question 12

crevice binders

Answer 12

used to stabalize destabalized protein mutatnts, bind to destablized protein adn stabalize the correctly folded state.

Question 13

MDM2 blockers

Answer 13

blocks interaction between p53 and MDM2(the e3 ubiquitin ligase that recognizes p53. does not fix the misfolding of the p53, but as least some p53 will be unbound to mdm2, and hopefully some will be functional.

Question 14

Synthetic Metallochaperones

Answer 14

syntehtic chaperones transport Zn+2 into the cell, and then buffer cellular ZN+2 at the right concentration for p53 to bind at correct spot, despite its lowered zinc binding affinity mutation