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109305
Protein misfolding
Description
Protein Form and Function Mind Map on Protein misfolding, created by sophie_connor on 26/05/2013.
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protein form and function
protein form and function
Mind Map by
sophie_connor
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sophie_connor
over 11 years ago
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Resource summary
Protein misfolding
Overview
When does it go wrong?
Protein synthesis
Protein degradation
Why does it go wrong?
Mutation in protein
Lack of enzyme needed for correct folding
Accumulated damage to protein
Conformational change
Conformational diseases
If a protein misfolds it should be removed by degradation
What happens in disease as a result?
Protein is non-functional
Protein is lacking or in short supply
Protein is in the wrong place
Aggregates accumulate causing disruption
Aggregation
Protein self-assembles and forms aggregates
Protein misfolding and disease: Aggregation and degradation
Protein is no longer in the right place to be functional
Misfolding occurs during protein synthesis and folding causing loss of function
Cystic fibrosis
1/2000 live births
Autosomal recessive
200 different mutations
CFTR
A plasma membrane chloride channel in epithelial cells
An ABC transporter
An enzyme that utilises ATP
Many components needed to fold for the protein to be functional
Hence lots of mutations
Folding pathway
Complicated due to many subunits
Different points of folding
Co-translational folding where folding occurs during synthesis
Post-translational folding where all components are put together
Deletion of F508
CFTR folds poorly
Degraded in endoplasmic reticulum
F508 usually forms a hydrophobic pocket and is important in protein folding
Mutant F508 CFTR accumulates in endoplasmic reticulum
Does not attach to plasma membrane
Molecular consequences of CFTR mutations
No CFTR synthesis
Non sense mutation
Deletion of TT
Change in splice junction
Block in processing
Missense mutation
AA deletion
Block in regulation
Missense mutation
Altered conductance
Missense mutation
Reduced synthesis
Missense mutation
Alternative splicing
Serpins and disease
Serpins
Serine protease inhibitors
Alpha-1-antitrypsin
Antithrombin
Cell conserved structure
3 beta sheets
9 alpha helices
Reactive centre loop
Negatively unfolded
Serpin mechanism
Protease will cleave reactive centre loop
Inhibitor changes molecule conformation
Reactive centre loop becomes beta strand
Protease is denatured
Conformational change opens up the protein for misfolding
Serpin polymerisation
Occurs in conformational diseases
Alpha-1 ant-trypsin is a protease inhibitor in the lungs
Without protease the lungs are susceptible to emphysema
Serpin polymers
alpha1-antitrypsin forms filaments which have beads on a string appearance
Hyperthermostable
Polymer formation is irreversible
Alpha1-antitrypsin is made in the liver
Transported to lungs
Forms aggregates
Causes liver disease
Loss of function in lungs causes emphysema
Alpha-1 anti-trypsin deficiency
Acute phase protein
Overexpressed following inflammation
1 in 20 hetereozygous
Homozygotes suffer from emphysema and liver disease
Z alpha1-anti-trypsin
Replaced glutamate for lysine
Results in loss of salt bridge
Affects beta sheet where reactive loop inserts
Reactive centre loop of another molecule is able to insert into this gap
Circular dichroism shows structures of alpha1 and zalpha1
Very similar
Tertiary structure has aromatic residues in different environments
Protein misfolding and disease: Aggregation and acculumulation
Disease related to accumulation of deposited material and disruption of tissues
Amyloid
Insoluble fibrils formed by polymerisation of normally soluble proteins
Deposited in tissue
Large number of proteins can form amyloid fibrils
Proteins are all different to each other and cause different diseases
Amyloid formation involves a conformational change in the native protein
What makes a native protein aggregate form amyloid in disease?
Mutations
Destabilises structure making them more likely to form amyloid fibrils
High concentration
Infections
Amyloid fibrils formed from different proteins have similar structures
Congo red staining
EM
Shows long, straight, unbranching fibrils
X-ray fibre diffraction
Shows charcteristic cross beta diffraction pattern
Amyloid fibrils can be defined in different ways
Structure of proteins
Grow a crystal and use diffraction pattern to tell you arrangement of atoms
Fibre diffraction and cross beta structure
Diffraction patterns form specific fingerprint
Repeating structure revealed where beta sheets are joined by hydrogen bonds
Structure of amyloid
Fibrils are made of several protofilaments that are formed by many beta sheet structures
Negative design of natural beta proteins
Proteins avoid potential beta assembly
Edge of beta sheets are protected with beta bulges
Beta sandwich proteins
Beta bulge causes twist in edge strand preventing hydrogen bonding upon elongation
Inward pointing charged side chains
Aggregation leads to burial of charge which is energetically unfavourable
Helix at the end of beta sheet preventing it from associating with other beta sheets
Amyloid fibres consist of a mixture of fibrils
Lots of short peptides form amyloid fibrils
Fibre diffraction analysis used to see how peptides pack together
Crystal structure of amyloid
Must be soluble and hetereogenous, in solution and correct environmental conditions
To find if the crystal structure is representative of the amyloid fibre oberve under electron microscope
Compare 2 crystals structures by comparing fibre diffraction and electron micrographs
Alzhiemers and brain degeneration
Memory loss and personality changes
Most common form of dementia
Sporadic AD: patients over 70
Familial AD: 30-40 years
Large vacuoles appear in brain tissue
Accumulation of Alzheimers peptide AB
AB cleaved from amyloid precursor protein (APP)
APP is a membrane protein
Cleaved by secretases
Everyone has AB
Amount of AB affects the chance of a person developing Alzheimers
Monomeric protein
When aggregates it results in a toxic oligomer
Forms toxic protofibrils
Results in amyloid fibres
Form amyloid plaques
Amyloid plaques made of amyloid fibrils accumulate in the brain
Composed of cross beta structure
Forms gradually twisting structure
Neurofibrillary tangles
In cell bodies of neurons
Composed of paired helical filaments and tau
Associated with neuronal degradation and cell death
Extracellular in the neutrophil
Less efficient at protein folding with age
Genetic predispositions
Presenlin 1/2
Secretases involved in the production of AB
ApoE4
More likely to get Alzhiemers than someone with ApoE2
Environmental factors
Trauma
Inflammation
Infectious proteins-prions
Prions form amyloid fibres
Mad cow disease and Creutzfelt Jakob disease (CJD)
Normal cellular prion is not a beta sheet structure
Normal form can be transformed into infectious by toxic infection
Mechanism requires a host protein to be infected
Build up leads to increase in aggregation
Prion hypothesis
A toxic oligomer in one cell can spread to others
How is the amyloid toxic and transmitted?
Cellular membranes
AB has retained the ability to work within the membrane from its precursors
Seeding/template aggregation
AB needs to move from cell to cell
Test for the effects of AB
AB affects lipid membranes
Use biometric lipid vesicles
Vesicles have fluorescent dye inside them which only fluoresces when released
AB comes along and disrupts the membrane
Fluorescent dye leaks out and this can be measured
As AB assembles it becomes less able to permeate membranes
Atomic force microscopy of planar membranes
Shows permeation by AB
AB42 oligomers are toxic to neuronal cells when added and incubated for 24 hours
Antibody labelling
Show accumulation
Electron microscopy
AB accumulates on surface of neuroblastoma cells and is internalised
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