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To Fold or to Misfold: What is the Problem? (Molecular Origami) - - PowerPoint PPT Presentation
To Fold or to Misfold: What is the Problem? (Molecular Origami) - - PowerPoint PPT Presentation
To Fold or to Misfold: What is the Problem? (Molecular Origami) Sheena E Radford Astbury Centre for Structural Molecular Biology University of Leeds Proteins Fold to Amazingly Complex Structures! The Protein Folding Problem: How is the
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Nature’s Origami: Cracking the Folding Code
Chris Anfinsen Nobel Prize 1972
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Proteins Fold to Amazingly Complex Structures!
.. from only their amino acid sequences
It is an amazing feat of evolution that proteins fold and assemble in the cell rapidly and efficiently. Diseases associated with protein misfolding, whilst rare in terms of protein sequences, are a major threat to human health today
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Diseases of Protein Misfolding: a Major Threat
- More than 50 known protein
aggregation-based diseases.
- Includes two of the most prevalent
and life-threatening diseases of the developed world – Alzheimer’s disease and Type II diabetes.
- Enormous economic and social
burden.
- Diagnosis/prognosis difficult,
therapies either poor or not currently available
Sources: CDC; Projection of the year 2050 burden
- f diabetes in the US population;
Alzheimer’s Study Group, National Alzheimer’s Strategic Plan, NIH.
Type II diabetes Alzheimer’s disease
Cost in $Bn Cost in $Bn
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Neurodegeneration Systemic/ Localised Amyloidosis Pathogen Infectivity Cancer
Type II Diabetes
- Amylin/IAPP
Alzheimer’s Disease
- Aβ
Parkinson’s Disease
- α-synuclein
Dialysis related amyloidosis
- β2-microglobulin
Transmissible spongiform encephalopathy
- Prion
Cardiac amyloidosis
- e.g. Immunoglobulin
light chain
Light chain amyloidosis Medullary thyroid cancer
- Calcitonin
Atherosclerosis
- Apolipoprotein A1
- Immunoglobulin light chain
Amyloid Disorders: A Large Class of Diseases
Machado Joseph Disease
- ataxin 3
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How do proteins fold? How do proteins misfold? How does protein misfolding affect cells? Can we use structural molecular knowledge to combat disease?
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Diseases of Protein Misfolding
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Jimenez, Saibil et al. Sawaya, Eisenberg et al. Wasmer, Riek, Meier et al. White, Saibil, Radford et al. Sheynis, Radford et al. Milanesi, Saibil, Radford et al. Saibil et al.
Amyloid fibrils: Beautiful, Yet Deadly Structures
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Amyloid fibrils: Beautiful, Yet Deadly Structures
Which sequence / structural /cellular factors promote folding versus aggregation ? What happens to tip the balance ? How can we use this knowledge to combat disease ?
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Molecular Dissection of Amyloid Formation
The goal is to determine the nature of the folding and aggregation landscapes in atomistic detail. Use biochemical, biophysical, cell biological, computational methods
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β2-microglobulin: Dialysis Related Amyloidosis
(Nature SMB, 2002, 2006, Mol Cell 2011, 2014)
β2m
a myloid fibril
(White , 2009)
MHC c la ss I α2 α1 α3 β2m
(T r inh 2002 1L DS)
β2-microglobulin, essential for immunity, aggregates and causes disease
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Molecular Dissection of Amyloid Formation
(Nature SMB, 2002, 2006, Mol Cell 2011) Solving the folding pathway Thomas Jahn
Isomerisation
- f only a
SINGLE peptide bond initiates aggregation
Fibril
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Mass Spectrometry: Seeing Oligomers
(PNAS 2010, Nature Chem Biol, 2011) With Prof Alison Ashcroft (UoL)
Native Mass Spectrometry: A new tool for screening and classifying amyloid inhibitors that target defined species
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NMR: Amyloid Formation in Atomic Detail
(Molecular Cell, 2014)
Protein Folding Intermediates: Dangerous potentially infectious materials
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Nature’s Origami: Cracking the Folding Code
Chris Anfinsen Nobel Prize 1972
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