Protein Folding Diseases (Karagoz)

Question 1

Explain cystic fibrosis (CF) in terms of protein folding.

Answer 1

Lung epithel:
- CFTR transfers ions thorugh plasma membrane in lungs
- CFTR delF508 -> misfolding -> uneven conc. of ions and water -> Hsp90 + AHA1 degrade it
- AHA1 inhibitors stop the degradation and maintain partial function of the protein -> sufficient

Question 2

Explain Src kinase cancer in terms of protein folding.

Answer 2

In Src cancer:
- Src constitutively active (oncogene) because autoinhibitory function lost
- activation dependent on Hsp90
- Hsp90 inhibition

Question 3

Explain aneuploidy in terms of protein folding.

Answer 3

• dimers are expressed stochiometrically: from both chromatids
• aneuploidy: disturbed balance in dimer expression and rise of orphan subunits that have no pairing -> aggregation
• Hsp90 inhibiition -> less Hsp90 and more HSP TFs -> more Hsp90

Question 4

How can Hsp90 be inhibited<

Answer 4

• N-term. targetting drug: ATP binding inh.
• C-term. targetting: dimerization impairment
• isoform selective inhibition: obtain Hsp90 that only bind in cytosol / mitochondria / ER / specific proteins