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Chaperones and protein folding

Chaperones and protein folding. Randy Hampton. 2100 E Pacfic Hall. rhampton@ucsd.edu. The folded state of protein. The folded state of protein. Christian Anfinsen (Nobel 1972). The linear sequence of biological proteins have sufficient information for the folded state.

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Chaperones and protein folding

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  1. Chaperones and protein folding Randy Hampton 2100 E Pacfic Hall rhampton@ucsd.edu

  2. The folded state of protein

  3. The folded state of protein Christian Anfinsen (Nobel 1972) The linear sequence of biological proteins have sufficient information for the folded state

  4. Anfinsen experiment(s)

  5. BUT This is a thermodynamic, not kinetic, fact The folded state of protein Christian Anfinsen (Nobel 1972) The linear sequence of biological proteins have sufficient information for the folded state

  6. Protein folding requires a kinetic pathway

  7. The search for a folded conformation

  8. E represents the energy of the system Q is defined as the proportion of native contacts formed P is a measure of the available conformational space.

  9. During folding things can go wrong correct aggregate misfolded

  10. The cell is not a biochemist... When preparing a protein a biochemist likes Cold temperatures High purity Concentration in the 1-2 mg/ml range No environmental insults

  11. The cell is not a biochemist... Inside the cell conditions are 37 oC 1000s of other proteins Incredibly high concentrations (200-300 mg/ml) Continuous internal and external insult

  12. Chaperones to the rescue Bind misfolded proteins Various groups Essential for life Found in all 3 domains Often use ATP in their action

  13. Chaperone function 101 Holder or Folder

  14. Chaperone function 101 Holder no chaperone plus DnaK KERN, HOLMGREN and RICHARME Biochem. J. (2003) 371 (965–972)

  15. Chaperone function 101 Holder function in transmembrane delivery chaperones

  16. Chaperone function 101 Folder KUSMIERCZYK and MARTIN Biochem. J. (2003) 371 (669–673)

  17. Chaperones participate in many actions folding and refolding preservation of unfolded state facilitation of transport block to aggregation disaggregation degradation assembly/dissembly of oligomeric complexes facilitation of signaling processes

  18. (Some) Types of chaperones Hsp70 Hsp60 chambered chaperonins Hsp90 Small heat shock proteins (sHsp) Co-chaperones

  19. Hsp70 or DnaK Monmeric proteins N-terminal ATPase domain C-terminal substrate binding domain Operates as a monomer (but...) 10-20% of de novo folding in bacteria

  20. Hsp70 or DnaK

  21. Hsp70 or DnaK

  22. Hsp70 ATPas: low and high affinity cycling

  23. The truth about Hsp70 action

  24. Some of the prototype Hsp70s DnaK in bacteria, mitochondria, and chloroplasts BiP in eukaryotic ER Hsc70 in eukaryotic cytosol

  25. Hsp60 chaperonins: chambered chaperones GroEL (bacterial and mito/chloro)) TRiC (eukaryotic cytosol)

  26. Hsp60 chaperonins: chambered chaperones GroEL (bacterial and mito/chloro))

  27. Hsp60 chaperonins: chambered chaperones GroEL (bacterial and mito/chloro))

  28. Hsp60 chaperonins: chambered chaperones GroEL (bacterial and mito/chloro))

  29. Hsp60 chaperonins: chambered chaperones GroEL and GroES (bacterial and mito/chloro))

  30. Hsp60 chaperonins: chambered chaperones GroEL and GroES (bacterial and mito/chloro))

  31. Hsp60 chaperonins: chambered chaperones GroEL and GroES (bacterial and mito/chloro))

  32. Hsp60 chaperonins: chambered chaperones TRiC (eukaryotic cytosol)

  33. Hsp60 chaperonins: chambered chaperones TRiC (eukaryotic cytosol)

  34. Co-operation of chaperones is common Groups of chaperones will cooperate to fold or do other functions These interactions can create mulitple pathways Can be different for different substrates Can be different for different physiological circumstances

  35. bacterial folding

  36. eukaryotic folding

  37. Hsp90 chaperones

  38. Hsp90 chaperones

  39. CFTR: a transmembrane folding nighmare

  40. CFTR: a transmembrane folding nighmare

  41. CFTR: a transmembrane folding nighmare

  42. Small Heat Shock Protein: alpha crystallins

  43. Small Heat Shock Protein: alpha crystallins

  44. Small Heat Shock Protein: alpha crystallins

  45. Small Heat Shock Protein: alpha crystallins

  46. Co-chaperones work with chaperones DnaJ or Hsp40: stimulate ATPase activity of Hsp70 and mediate substrate loading Bag proteins stimulate ADP/ATP exchange GroES works with GroEL to cap chamber CHIP creates a ubiquitin ligase

  47. The truth about Hsp70 action

  48. Co-chaperones work with chaperones

  49. Diseases of folding Amyloid syndromes: Huntingtons, Alzheimers, etc Retinopathies Normal ageing and misfolded proteins Many mutants cause misfolding that leads to phenotypes

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