Protein misfolding & diseases
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Protein synthesis and disposal occur in highly regulated manner. In cells protein folding is assisted by special kind of proteins called as molecular chaperones and disturbances in protein quality control leads to deadly diseases
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Protein misfolding & diseases
- 1. SyamprasadNP
- 2. 2 CONTENTS.... 1. INTRODUCTION 2. PROTEIN STRUCTURE 3. FUNCTIONS OF PROTEINS 4. PROTEIN SYNTHESIS 5. FATE OF PROTEINS 7. REGULATION 8. CHAPERONE 9. PROTEIN QUALITY CONTROL 10. WHAT IS MISFOLDING 11. DISEASES 12. CYSTIC FIBROSIS 13. TYPE2 DM 14. TARGETS 15. CONCLUSION
- 3. INTRODUCTION Proteins are the most important macromolecules in living cells. Almost everything that occurs in the cell involves one or more protein. Protein is a polypeptide. Amino acids are the building blocks of proteins. Proteins performs many functions in living organism. The functions of a protein depend on its amino acids sequence. 3
- 4. FUNCTIONS OF PROTEINS According to function protiens are... 4 Enzymes Defense proteins Regulatory proteins Transport protein Structural proteins Contractile proteins Lim, L. 'Mechanisms, Regulation And Special Functions Of Protein Synthesis In The Brain'. FEBS Letters 97.2 (1979): 385.
- 5. 5 PROTEIN SYNTHESIS DNA TRASCRIPTION mRNA Pre mRNA RNA Processing TRANSLATION NUCLEUS RIBOSOME FOLDING FUNCTIONAL PROTEIN RER PROTEIN Lim, L. 'Mechanisms, Regulation And Special Functions Of Protein Synthesis In The Brain'. FEBS Letters 97.2 (1979): 385.
- 6. Often translation is not sufficient to make a functional protein. Sometimes other molecules are also attached to the polypeptides: sugars, lipids, phosphates, etc. Polypeptides fold spontaneously into their active configuration. Some times the so formed proteins may misfolded (20%) 6 FATE OF PROTEINS... S. Walter Englander1*, Leland Mayne1 and Mallela M. G. Krishna1,2 Proteinfolding and misfolding : mechanism and principles, Quarterly Reviews of Biophysics; 2008 Vol 40(4), 287-326
- 7. 7 What is folding??? Primary structure Secondary structure Tertiary structure Hydrogen bond Disulphide bond S. Walter Englander1*, Leland Mayne1 and Mallela M. G. Krishna1,2 Proteinfolding and misfolding : mechanism and principles, Quarterly Reviews of Biophysics; 2008 Vol 40(4), 287-326
- 8. 8 What is misfolding ??? Native protein A. Hydrophobic parts will be assembled inside and hydrophilic will be out side B. α–helix will be much more than β–plated sheet Misfolded protein A. More hydrophobic part will express outside B. α–helix will be less than β–plated sheet S. Walter Englander1*, Leland Mayne1 and Mallela M. G. Krishna1,2 Proteinfolding and misfolding : mechanism and principles, Quarterly Reviews of Biophysics; 2008 Vol 40(4), 287-326
- 9. Cellular environment is very crowded. Possibilities for several interaction. Several possibilities for misfolding. Still protein folds in proper manner which is difficult to see in invitro condition. In cells protein folding is assisted by special kind of proteins called as molecular chaperones. 9 REGULATION Christopher J. Roberts, Therapeutic Protein Aggregation: Mechanisms, Design, and Control, Trends Biotechnol. 2014 July ; 32(7): 372–380.
- 10. “An older person who accompanies young people at a social gathering to ensure proper behavior” Chaperons protect proteins from interfering interactions during folding It help proteins in their folding process. By providing right cellular environment. Unfold misfolded proteins. 10 CHAPERONE...... Chaudhuri TK, Paul S. Protein-misfoldingdiseases and chaperone-based therapeutic approaches. FEBS Journal 2010; 1331-1349.
- 11. Selectevely bind to unfolded or misfolded proteins by hydrophobic interactions Chaperon CHAPERONE...... ATP ADP Native protein Unfolded protein 11Chaudhuri TK, Paul S. Protein-misfoldingdiseases and chaperone-based therapeutic approaches. FEBS Journal 2010; 1331-1349.
- 12. CLASSIFICATION Heat shock protein 70/DnaK Heat shock protein 90,100,124 Small heat shock proteins GroEL ,GroES Heat shock protein 40/DnaJ 12 CHAPERONE...... Chaudhuri TK, Paul S. Protein-misfoldingdiseases and chaperone-based therapeutic approaches. FEBS Journal 2010; 1331-1349.
- 13. 13 PROTEIN QUALITY CONTROL Unfolded protein Holding chaperone Folding chaperone Unfolding chaperone Ubiquitin proteasome Native protein protein aggregates Misfolded protein Degraded polypeptide Unfavorable condition Fibrils Protein deficiency disorderProgression to disease or toxicity R. J. Mayer, A. Ciechanover, M. Rechsteiner, Protein Degradation, Vol. 2: The Ubiquitin-Proteasome System, KGaA, Weinheim ISBN, 2009: 3-527
- 14. 14 CAUSES FOR MISFOLDING Mutation Temperature Altered cell chemistry Metal ions Protein Concentration Crowding Oxidative Stress Misfolded protein S. Walter Englander1*, Leland Mayne1 and Mallela M. G. Krishna1,2 Proteinfolding and misfolding : mechanism and principles, Quarterly Reviews of Biophysics; 2008 Vol 40(4), 287-326
- 15. 15 PROTEIN MISFOLDING DISEASES Diseases Protein involved Alzheimer‘s disease Amyloid-β,Tau Parkinson disease α-Synuclein Diabetes type 2 IAPP Amylotrophic lateral sclerosis Superoxide dismutase Cystic fibrosis CFTR Sickle cell anemia Hemoglobin Hungtington disease Huntingtin Creutzfeldt-Jakob disease Prion protein Amyloidosis Ten other proteins Heart disease Desmin Chaudhuri TK, Paul S. Protein-misfoldingdiseases and chaperone-based therapeutic approaches. FEBS Journal 2010; 1331-1349.
- 16. 16 Defficiency of functional protein Forms insoluble aggregates PROTEIN MISFOLDING DISEASES Cystic fibrosis, Marfan syndrome, amylotrophic lateral sclerosis Alzheimer’s,Parkinson’s, Type2 diabetes and many more Chaudhuri TK, Paul S. Protein-misfoldingdiseases and chaperone-based therapeutic approaches. FEBS Journal 2010; 1331-1349.
- 17. In T2DM Amylin misfolding and Aggregation and death of β- cells. Newer study-96% of T2DM patient having IAPP aggregates Translation of IAPP gene occurs In the absence of significant ER stress, chaperones are able to properly fold IAPP. 17 TYPE2 DIABETIC MELLITUS
- 18. In the presence of significant ER stress 18 TYPE2 DIABETIC MELLITUS IAPP misfolding IAPP oligomers chaperon Islet amyloid Ubiquitin-proteasome apoptosis Beta cell death Melvin R Hayden et.al Type 2 Diabetes Mellitus as a Conformational Disease, JOP. J Pancreas (Online) 2005; 6(4):287-302.
- 19. Desmin is a protein maintaining z-disc in myocardial muscle filaments. Mutation in gene coding for desmin pN116s, pE114del. Chaperons anable to correctly fold mutated desmin. Misfolding and aggregation. 19 HEART DISEASES
- 20. misfolded proteins could easily interfere with either cell metabolism or the inherent function of a cardiomyocyte. Leads to repeated cycles of uncontrolled contraction and relaxation. 20 HEART DISEASES Xuejun Wang, Jeffrey Robbins; Heart Failure and Protein Quality Control, American Heart Association.Inc, October 30, 2012.
- 21. 21 Upregulation of molecular chaperones. Pharmacological chaperones Inhibit protein aggregation Upregulation of Ubiquitin proteasome system TARGETS...
- 22. Protein is an major component of our body and its synthesis and disposal occur in highly regulated manner In cells protein folding is assisted by special kind of proteins called as molecular chaperones. Disturbances in protein quality control leads to deadly diseases Unwinding the secrets of proteins can open a new path for drug discovery 22 SUMMARY