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109207
Protein misfolding
Descrição
BSc Protein Form and Function Mapa Mental sobre Protein misfolding, criado por Jen Harris em 26-05-2013.
Sem etiquetas
protein form and function
protein form and function
bsc
Mapa Mental por
Jen Harris
, atualizado more than 1 year ago
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Criado por
Jen Harris
mais de 11 anos atrás
54
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Resumo de Recurso
Protein misfolding
Overview
When?
Protein synthesis
Protein degradation
Sometimes small fragments will associate with one another instead of being fully degraded
Why?
Mutation in protein
Lack of enzyme needed for correct folding
Accumulated damage to protein
Become less efficient
Conformational changes
Impact
Protein is non-functional
Protein is lacking or in short supply
Protein is in the wrong place
Aggregates can accumulate and cause disruption
Aggregation and degradation
Type 1 procollagen
Osteogenesis imperfecta
alpha1-antitrypsin
Deficiency
CFTR
Cystic fibrosis
1/2000 live births
Autosomal recessive
Epithelial plasma membrane chloride channel
ABC transporter
200 different mutations
May account for commonness of condition
We make significantly more than we need because misfolding is so common
Co-translational folding
During synthesis, on the ribosome
Post-translational folding
F508 CFTR doesn't accumulate but is degraded in the ER
The change is so minimal, but it affects the key S7-H6 loop
Types of mutation
Type I: No synthesis
G542X
Type II: Block in processing
delta-F508
Type III: Block in regulation
Missense G551D
Type IV: Altered conductance
MIssense R117H
Type V: Reduced synthesis
MIssense A455E
LDL receptor
Familial hypocholesterolaemia
Serpins
SERine Protease INhibitors
alpha1-antitrypsin
Mutation
Emphysema
Liver disease
Acute-phase protein
Overexpressed following mutation
1 in 20 northern Europeans heterozygous for Z-allele of alpha1-antitrypsin
Loss-of-function, 60% inhibitory activity retained
Replacement of acidic glutamine for basic lysine
Loss of salt bridge
Where the reactive centre loop opens up
Homozygosity
Emphysema
Liver disease
EM
Filaments in "beads-on-a-string" formation
Consistent with assembly into polymers
PAGE
Native runs as a ladder
Because all different length chains have assembled
Circular dichroism analysis
Z form has less pronounced peaks and troughs
Central aromatic residues in different environments
alpha1-antichymotrypsin
Antithrombin
Large family
Look similar
Quite different roles
Structure well conserved
3 beta-sheets
9 alpha-helices
Reactive centre loop
Important for function
Natively unfolded
Mutations
Dementia
Neuroserpin
Mechanism
Cleaved by protease. Brings one side down and inserts into reactive beta sheet. Opens protein for misfolding whilst denaturing the protease
Polymer formation is irreversible
Serpin polymers are hyperthermostable
Aggregation and accumulation
Amyloidoses
Amyloid
Insoluble fibrils that are formed by polymerisation of normally soluble proteins and are deposited in the tissues.
Intra- or extracellular
Smooth and not recognisable as original proteins
Fibrils formed from different proteins have very similar structures
Stain with Congo Red, green birefringence under cross-polarised light
There is a particular ordering of the dye molecules
EM
Long
Straight
Unbranching
X-ray
Cross-beta diffraction pattern
Repeating structure
A ladder of beta-sheets running perpendicular to the vertical axis
There are many different proteins found
Extracellular
Transthyretin
Gelsolin
Lysozyme
Intracellular
alpha-synuclein
Tau
Beta-sheet
Alpha-helical
Alpha/beta
Peptides
It's such an organised structure that it works for any size of protein
Causes
Mutations
Transthyretin
High concentration
Immunoglobulin
Infectious
Prion
CJD
1. Monomer
2. Aggregate
3. Oligomer
4. Protofibril
5. Amyloid fibril
6. Amyloid plaque
Protofilaments are individual fibres that wrap around one another
Huntingtin
Huntington's disease
Alpha1-antitrypsin
Deficiency
Alpha-synuclein
Parkinson's
Cu/Zn superoxide dismutase
ALS
Disease relates to accumulation of deposited material and disruption of tissues
Cell death
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