GOOD MRNING
GODO MRONING

GOOD MORNING
Proteins
Diversity of Proteins
Hemoglobin
Hormones
Enzymes
Antibodies
Collagen…………
 If there is a job to be done in the molecular
...
“ Proteins are the work horses of the cell”
Hence
How did the first protein originate?
Origin of Life
Iam the author of “History of Humanity”
Frederick Banting
Hugo Theorell
Earl W Sutherland
Gerald M Edelman
Rodney Porter
Rosalyn S Yalow
Alfred G Gilman
Martin Ro...
What is Protein folding ?
Structural Levels of Proteins
Primary Secondary
Protein stability
 The extreme diversity in their chemical and
physical properties is achieved due to the
variety in thei...
Protein stability
 The situation becomes more complicated
since this stability must be ascertained in
a certain range of ...
• Hydrogen Bonding
• Vander Waals interactions
• Ionic strengths
• Disulfide bonds
 Hydrophobicity: the dominant
force in...
Protein Denaturation
 The activity of a protein depends on its
three-dimensional structure.
 Intramolecular bonds, espec...
Protein Denaturation with
extreme pH or Temp.
Folding a protein on a computer with a full-atom
model in explicit solvent has been termed the
'holy grail' of the protein...
“The Quest for Holy Grail”
unfolding refolding
Anfinsen - Nobel Prize 1972
8M urea
Dilution of
denaturant
“ Ribonuclease ”
Break through…
Protein denaturation by temperature
R John Ellis
Current Opinion in Structural Biology 2001, 11:114–119
Macromolecular crowding
Invitro refolding of a Protein
Native
UnfoldedProtein with 100 amino acid residues
Assume 2 conformations for each residue
2100
possibilities
1010
years ...
Folding models:
 Framework model
 Hydrophobic collapse mode
 Nucleation condensation model
Folding is a stepwise process
Local secondary structures forms first and this is
Followed by longer range interactions
A stably folded proteins has…..
 Hydrophobic side chains buried
 Charged side chains on the surface
 Cysteine’s form Co...
Free energy funnel
Native structure
 Mutations
 Premature termination of Translation
 Fault in post-translational modifications
 Strong Promoters
 High I...
ALL CELLS
ALL ORGANISMS
Living in the World
Must cope with…
Stress !!!
What is stress?
 In biology, stress is the driving force
behind the process of adaptation and
evolution.
Driven by inner need and Stress
Interesting story
F. Ritossa –1960 discovered the heat shock
(HS) response while observing the salivary
cells of Drosophil...
Temp
environ
Temp
cell
Folded
Proteins
Unfolded
Proteins
Aggregates
Loss of Protein
Function
Network
failure
Death
Cell
How do Chaperones work?
 Heat shock proteins stabilize proteins and
are involved in the folding of denatured
proteins
Hsp 100
Hsp 90
Hsp 60
Hsp 70
Small
Hsp’s
Hsp 40
Family Major Functions
Protein disaggregation, thermotolerance
Regulatory ...
 Other inducers of the heat shock proteins:
 Oxidizing agents
 Metals
 Sulfhydryl reagents
• Poisonous gases…………
The Nobel Prize
Chemistry 2004
"Kiss of Death"
 Aaron Ciechanover,
 Avram Hershko,
 Irwin Rose
Exit
Entry
Protein misfolding Diseases
Protein misfolding diseases can be classified
in to two categories
 Diseases caused due to th...
Disease Protein Involved
Cystic Fibrosis CFTR
Retinitis pigmentosa Rhodopsin
Cancer p53
Osteogenesis
imperfecta
Type 1 pro...
Polymerized Sickle Hemoglobin
Sickle-cell anemia
Sickle shaped RBC
Retinitis Pigmentosa
Normal Vision
Retinitis Pigmentosa
 Gene codes for a protein, CFTR, which is
chloride ion channel.
 Small fraction of protein matures to the cell
surface
...
Osteogenesis imperfecta
Disease Protein involved
Alzheimer’s Disease Amyloid β- peptide
Huntington Disease Huntington protein
Spongiform
encephalo...
Prion infected Brain of a cattle
Bovine Spongiform Encephalopathy
Prion Protein
Prion diseases
 Human - Kuru & CJD
 Sheep - Scrapie.
 Cow - Mad Cow disease
Kuru
Victim
Mad
Cow
“I Have Completely Forgotten
Why I came Upstairs “
Alzheimer’s Disease
Summary
Proper folding of proteins is essential for a
cell to carry out Its normal cellular function
 Misfolded proteins ...
Why study protein folding?
Understanding Protein folding in vivo helps
in adapting them in invitro and Insilco
 Molecular...
Mobile phones, heat shock proteinsMobile phones, heat shock proteins
and cancerand cancer
Mobile phone use
Absorption of energy in to brain tissue
Protein unfolding
Heat shock response
Heat shock proteins induced...
Thank you
Supplementary
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
Protein folding, Heat shock proteins and disease involved with protein misfolding
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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

Protein folding, Heat shock proteins and disease involved with protein misfolding

  1. 1. GOOD MRNING GODO MRONING 
  2. 2. GOOD MORNING
  3. 3. Proteins
  4. 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. 5. “ Proteins are the work horses of the cell” Hence
  6. 6. How did the first protein originate? Origin of Life
  7. 7. Iam the author of “History of Humanity”
  8. 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
  9. 9. What is Protein folding ?
  10. 10. Structural Levels of Proteins Primary Secondary
  11. 11. 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
  12. 12. 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.
  13. 13. • Hydrogen Bonding • Vander Waals interactions • Ionic strengths • Disulfide bonds  Hydrophobicity: the dominant force in protein folding Forces involved in Protein stabilisation
  14. 14. 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
  15. 15. Protein Denaturation with extreme pH or Temp.
  16. 16. 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?
  17. 17. “The Quest for Holy Grail”
  18. 18. unfolding refolding Anfinsen - Nobel Prize 1972 8M urea Dilution of denaturant “ Ribonuclease ” Break through…
  19. 19. Protein denaturation by temperature
  20. 20. R John Ellis Current Opinion in Structural Biology 2001, 11:114–119 Macromolecular crowding
  21. 21. Invitro refolding of a Protein
  22. 22. Native UnfoldedProtein with 100 amino acid residues Assume 2 conformations for each residue 2100 possibilities 1010 years of random searching Levinthal paradox (1968)
  23. 23. Folding models:  Framework model  Hydrophobic collapse mode  Nucleation condensation model
  24. 24. Folding is a stepwise process Local secondary structures forms first and this is Followed by longer range interactions
  25. 25. 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
  26. 26. Free energy funnel Native structure
  27. 27.  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`
  28. 28. ALL CELLS
  29. 29. ALL ORGANISMS
  30. 30. Living in the World
  31. 31. Must cope with…
  32. 32. Stress !!!
  33. 33. What is stress?  In biology, stress is the driving force behind the process of adaptation and evolution.
  34. 34. Driven by inner need and Stress
  35. 35. 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
  36. 36. Temp environ Temp cell Folded Proteins Unfolded Proteins Aggregates Loss of Protein Function Network failure Death Cell
  37. 37. How do Chaperones work?  Heat shock proteins stabilize proteins and are involved in the folding of denatured proteins
  38. 38. 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
  39. 39.  Other inducers of the heat shock proteins:  Oxidizing agents  Metals  Sulfhydryl reagents • Poisonous gases…………
  40. 40. The Nobel Prize Chemistry 2004 "Kiss of Death"  Aaron Ciechanover,  Avram Hershko,  Irwin Rose Exit Entry
  41. 41. 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
  42. 42. 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
  43. 43. Polymerized Sickle Hemoglobin Sickle-cell anemia
  44. 44. Sickle shaped RBC
  45. 45. Retinitis Pigmentosa
  46. 46. Normal Vision Retinitis Pigmentosa
  47. 47.  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
  48. 48. Osteogenesis imperfecta
  49. 49. 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
  50. 50. Prion infected Brain of a cattle Bovine Spongiform Encephalopathy
  51. 51. Prion Protein
  52. 52. Prion diseases  Human - Kuru & CJD  Sheep - Scrapie.  Cow - Mad Cow disease Kuru Victim Mad Cow
  53. 53. “I Have Completely Forgotten Why I came Upstairs “ Alzheimer’s Disease
  54. 54. 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
  55. 55. 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
  56. 56. Mobile phones, heat shock proteinsMobile phones, heat shock proteins and cancerand cancer
  57. 57. 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
  58. 58. Thank you
  59. 59. Supplementary

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