Protein folding, Heat shock proteins and disease involved with protein misfolding
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A complete understanding of protein folding, the role of Heat shock proteins and the ill effects of protein mis-folding
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Protein folding, Heat shock proteins and disease involved with protein misfolding
- 3. Proteins
- 4. Diversity of Proteins Hemoglobin Hormones Enzymes Antibodies Collagen………… If there is a job to be done in the molecular world of our cells, usually that job is done by a Protein
- 5. “ Proteins are the work horses of the cell” Hence
- 6. How did the first protein originate? Origin of Life
- 7. Iam the author of “History of Humanity”
- 8. Frederick Banting Hugo Theorell Earl W Sutherland Gerald M Edelman Rodney Porter Rosalyn S Yalow Alfred G Gilman Martin Rodbell Stanley Prusiner Aaron Ciechanover Avram Hershko Irwin Rose Wendell Meredith Stanley Paul D Boyer John E Walker Aaron Klug John Warcup Cornforth Christian B Anfinsen Stanford Moore William Stein Max Ferdinand Perutz John Cowdery Kendrew Frederick Sanger Arne W K Tiselius John Howard Northrop
- 10. What is Protein folding ?
- 11. Structural Levels of Proteins Primary Secondary
- 12. Protein stability The extreme diversity in their chemical and physical properties is achieved due to the variety in their properties of their building blocks Effort to design a protein with a specific function, nature has to solve an extremely difficult problem It needs be active and thermodynamically stable
- 13. Protein stability The situation becomes more complicated since this stability must be ascertained in a certain range of environmental conditions The native conformation of a protein is stable in a narrow range of temperature,pH, chemical composition of solvent, etc. ProteinpH Temp. Salt Conc.
- 14. • Hydrogen Bonding • Vander Waals interactions • Ionic strengths • Disulfide bonds Hydrophobicity: the dominant force in protein folding Forces involved in Protein stabilisation
- 15. Protein Denaturation The activity of a protein depends on its three-dimensional structure. Intramolecular bonds, especially hydrogen bonds, maintain the structure. Hydrogen bonds may break when the pH drops or the temperature rises above normal denaturing the protein
- 16. Protein Denaturation with extreme pH or Temp.
- 18. Folding a protein on a computer with a full-atom model in explicit solvent has been termed the 'holy grail' of the protein folding problem Berendsen HJC: Science 1998, 282: 642) A glimpse of the holy grail?
- 19. “The Quest for Holy Grail”
- 20. unfolding refolding Anfinsen - Nobel Prize 1972 8M urea Dilution of denaturant “ Ribonuclease ” Break through…
- 21. Protein denaturation by temperature
- 22. R John Ellis Current Opinion in Structural Biology 2001, 11:114–119 Macromolecular crowding
- 23. Invitro refolding of a Protein
- 24. Native UnfoldedProtein with 100 amino acid residues Assume 2 conformations for each residue 2100 possibilities 1010 years of random searching Levinthal paradox (1968)
- 25. Folding models: Framework model Hydrophobic collapse mode Nucleation condensation model
- 27. Folding is a stepwise process Local secondary structures forms first and this is Followed by longer range interactions
- 28. A stably folded proteins has….. Hydrophobic side chains buried Charged side chains on the surface Cysteine’s form Covalent disulfide bonds “All these features will contribute to Minimum” energy state Pack as close together as possiblePack as close together as possible Minimize contacts between hydrophobicMinimize contacts between hydrophobic groups and watergroups and water
- 29. Free energy funnel Native structure
- 30. Mutations Premature termination of Translation Fault in post-translational modifications Strong Promoters High Inducer concentrations Reasons for protein misfolding Loss of conformation due to stress`
- 31. ALL CELLS
- 32. ALL ORGANISMS
- 33. Living in the World
- 34. Must cope with…
- 35. Stress !!!
- 36. What is stress? In biology, stress is the driving force behind the process of adaptation and evolution.
- 37. Driven by inner need and Stress
- 38. Interesting story F. Ritossa –1960 discovered the heat shock (HS) response while observing the salivary cells of Drosophila and named them HSP’s My name is Chaperone
- 40. How do Chaperones work? Heat shock proteins stabilize proteins and are involved in the folding of denatured proteins
- 41. Hsp 100 Hsp 90 Hsp 60 Hsp 70 Small Hsp’s Hsp 40 Family Major Functions Protein disaggregation, thermotolerance Regulatory interactions with signaling proteins, stabilization of misfolded proteins Protein folding, membrane transport of proteins Protein folding (limited substrates in eukaryotic cytoplasm) Protein folding, co-chaperone for Hsp70 Stabilization of misfolded proteins, thermotolerance, eye lens structural proteins Functions of HSP families
- 42. Other inducers of the heat shock proteins: Oxidizing agents Metals Sulfhydryl reagents • Poisonous gases…………
- 44. The Nobel Prize Chemistry 2004 "Kiss of Death" Aaron Ciechanover, Avram Hershko, Irwin Rose Exit Entry
- 45. Protein misfolding Diseases Protein misfolding diseases can be classified in to two categories Diseases caused due to the misfolding or degradation of misfolded proteins Diseases caused due to accumulation of misfolded proteins
- 46. Disease Protein Involved Cystic Fibrosis CFTR Retinitis pigmentosa Rhodopsin Cancer p53 Osteogenesis imperfecta Type 1 procollagen Pro A Marfan Syndrome Fibrillin Sickle Cell anemia Hemoglobin Disease caused due to the misfolding or degradation of misfolded Protein
- 47. Polymerized Sickle Hemoglobin Sickle-cell anemia
- 51. Gene codes for a protein, CFTR, which is chloride ion channel. Small fraction of protein matures to the cell surface Mutation in protein CFTRΔF508 doesn't reach the cell surface. Cystic fibrosis
- 53. Disease Protein involved Alzheimer’s Disease Amyloid β- peptide Huntington Disease Huntington protein Spongiform encephalopathies Prion Protein Diseases caused due to the accumulation of misfolded protein
- 54. Prion infected Brain of a cattle Bovine Spongiform Encephalopathy
- 55. Prion Protein
- 56. Prion diseases Human - Kuru & CJD Sheep - Scrapie. Cow - Mad Cow disease Kuru Victim Mad Cow
- 57. “I Have Completely Forgotten Why I came Upstairs “ Alzheimer’s Disease
- 62. Summary Proper folding of proteins is essential for a cell to carry out Its normal cellular function Misfolded proteins can result in a wide variety of pathological conditions Existing therapies do not provide efficient cure for these Pathological conditions Small molecules called chaperones that increase the stability of the native state offer innovative therapeutic solution
- 63. Why study protein folding? Understanding Protein folding in vivo helps in adapting them in invitro and Insilco Molecular Drug design Protein-protein interactions Grastim Dengue vaccine
- 64. Mobile phones, heat shock proteinsMobile phones, heat shock proteins and cancerand cancer
- 65. Mobile phone use Absorption of energy in to brain tissue Protein unfolding Heat shock response Heat shock proteins induced HSP 27,40,70,90,110 Repeated mobile use Chronic expression of HSPs Induction of cancer Increased metastasis Inhibition of Apoptosis Resistance to anti cancer drugs Protein refolding
- 66. Thank you
- 67. Supplementary
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