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respiratory > Protein folding > Flashcards

Protein folding Flashcards

1
Q

do all the stages of replication need to be error free for proteins to work

A

yes

DNA needs to be without mutations that change the code
RNA needs to be properly transcribed without error
Protein need to be translated, folded and located in the correct part of the cell or outside it

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2
Q

what type of RNA binds each triplet of RNA bases

A

tRNA

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3
Q

what is the primary structure of proteins

A

linear sequence of amino-acids residues in the polypeptide chain
e.g. insulin has 2

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4
Q

what is the secondary structure of proteins

A

local folded structures
between atoms of backbone
most common structures are folding of alpha helix and beta bleated sheets

backbone

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5
Q

what type of bond holds beta pleated sheets and alpha helixes together

A

hydrogen bonds

pull on electrons and partial negative and partial positive charges causing folds and swirls

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6
Q

what is the tertiary structure of a protein

A

3D structure due to interactions between R groups of the amino acids that make up the protein
ionic bonds, polar forces , hydrophobic ( inside ) and hydrophilic , London dispersion forces and dipole and dipole
disulphide bonds - cysteine strongest

chain interactions

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7
Q

what is the quaternary structure of a protein

A

multiple polypeptide chains - also know as subunits

e.g. Hb -4 subunits alpha and beta

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8
Q

what process Is essential to move proteins to the right place on the membrane

A

protein translocation into the endoplasmic reticulum

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9
Q

how do membrane proteins enter membrane at the endoplasmic reticulum

A

signal recognition particle ( SRP) binds to newly synthesised peptide pausing protein synthesis.
until complex find SRP receptor on ER membrane. UPon docking the new peptide chain is inserted into the translocation channel. Protein synthesis will resume once SRP has been released from the ribosome.

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10
Q

5 steps of CFTR synthesis

A 
Transcription 
Translation and protein folding 
post-translational modification at the Golgi
protein trafficking 
surface expression of CFTR
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11
Q

what is this idea of quality control

A

not all protein may get to membrane or may not work when they get there due to cell having inbuilt system to deal with misfolded proteins

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12
Q

where does the control process fro CFTR happen

A

ER

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13
Q

if a protein is misfolded is it salvageable

A

yes can be refolded by chaperone proteins in the ER
However if a protein is terminally misfolded it is passed back through the ER membrane ( retrotranslocation ) into the cytoplasm where it is degraded by protease enzymes
two fates - recycled back or targeted foo degradation

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14
Q

How many classes of cystic fibrosis folding problems are there?

A

6

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15
Q

what is a class 1 CFTR protein mutation

A

nonsense( premature stop) mutation so a truncation mutation which means no functional protein is made so no CFTR protein

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16
Q

what is a class 2 CFTR protein mutation

A

missense mutation and the CFTR protein has become misfiled so it can’t traffic through the endoplasmic reticulum through the golgi to the cell membrane so it becomes degraded (substitution)(amino acid deletion)

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17
Q

example of a class 2 mutation

A

Phe508del

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18
Q

what is a class 3 CFTR protein mutation

A

protein gets to the cell membrane but docent function and won’t transport chloride ions - defective channel regulation
missense ( aa change)

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19
Q

example of a class 3 mutation

A

Gly551Asp

20
Q

what is a class 4 CFTR mutation

A

protein dosent fiction at cell membrane due to decreased channel conductance
missence aa change

21
Q

what is a class 5 CFTR protein mutation

A

only small amounts of proteins getting to the cell membrane so not much CFTR at the cell membrane to transport chloride
splicing defect - missence

22
Q

what is a class 6 CFTR protein mutation

A

protein gets to the cell membrane but it isn’t stable so it is quickly endocytose back into the cell and degraded
missence and aa change

23
Q

what is the most prevalent class mutation

A

2

24
Q

if I was to try and treat class 3 and 4 mutations what type of drug would I give and an example of this

A

potentiators

e.g. ivacaftor

25
Q

how could we treat a class 2 mutation

A

using a corrector such as lumacaftor with a potentiator ( ivacaftor)

26
Q

Severe genotypes of CFTR include patients who are homozygous (both genes have the same mutation) or compound heterozygous (the genes are different but both classed as severe genotypes) for what types of mutations

A

class I, II, III mutations.

27
Q

what is p.Phe508del mutation

what happens to the protein

A

deletion of 3 DNA bases resulting in a missing phenylalanine (F) amino acid at position 508 in the protein
so protein dosent fold properly
This misfolded CFTR is recognised by the cell’s quality control machinery and held in the ER and is then degraded

p.Phe508del can’t perform its function (as it doesn’t reach the plasma membrane of the cell) and this results in the symptoms of CF

28
Q

what is the p.Gly551Asp mutation

A 
Most common CFTR gating (class III) mutation, present in 4% of patients with CF
single nucleotide variant 
The protein gets to the cell membrane but it doesn’t function very well.

Result in the production of a CFTR protein that makes it to the cell membrane but does not open correctly.

“gating defect.”

29
Q

examples of chaperone( conformational folding or unfolding of proteins) proteins

A

Bip and calnexin

both in ER

30
Q

Ubiquitin function

A

small protein found in almost all cellular tissues regulates processes of other proteins - tagged fro degradation
proteasome degrades it

31
Q

Treatment for CF - limited to targeting the secondary effects of he defective CFTR protein

A 
Broncho diators, antibiotics and corticosteroids 
Pulmozyme , insulin and bisphosphates 
Vaccinations and flu jabs 
Enzymes , diet and nutrition 
Physiotherapy , airway clearance 
Lung transplantation
32
Q

what classes do potentiator drugs help

A

3 and 4

the rest need correctors and mixture

33
Q

what do potentiators do

A

increase the activity of defective CFTR at the cell surface. They either act on gating or conductance defects ( i.e. if gating enhanced opening and if conductance defect increase he flow of ions through CFTR)
regulating amount of fluids at the surface of the cell

34
Q

what do correctors do

A

overcome defective protein processing that normally result in the production of misfolded CFTR. This allows increased trafficking of CFTR to the plasma membrane

correctors increase the surface density of CFTR at the membrane. They may also enhance the function of CFTR at the membrane

35
Q

what are production correctors

A

these instruct the ribosomes to read through premature termination codons ( PTCs) during mRNA translation - these are for the ones when non proteins are made
read through agent promote the read through of premature termination codons in CFTR mRNA

the right stop codon is reached so a complete CFTR polypeptide is made and translated

36
Q

what does ivacaftor/kaleydeco do

A

increase opening time of the channel for type 3 and 4

37
Q

what were some of the clinical effects of ivacaftor in patients with at least one class 3 CFTR mutation

A

Increase ( approx 10% ) in FEV1 ( lung function)
Weight gain ( approx 2.8kg)
Decreased pulmonary exacerbations ( approx 50%)
Decreased sweat chloride concentration
Decreased endobronchial colonization with P.aeruginosa

38
Q

what is a QALY

A

quality-adjusted life year - assess value of medical interventions

39
Q

what percentage of people have class 3 mutation ?

A

3.9%

40
Q

what do correctors increase

A

the surface density of CFTR at the membrane - may also enhance the function of CFTR at the membrane

41
Q

what is orkambi

what effects did it have

A

ivacaftor/lumicaftor

Reduced pulmonary exacerbations
Increased BMI
Increased FEV1 - lung capacity

given over the age of 2

Lumicaftor in orkambi - induces enzyme that metabolises the ivacaftor drug so reducing that amount available
Tezacaftor - corrector - alternative corrector - symkevi - over age of 12 with that mutation or one of those functions

42
Q

what drugs are involved in the triple combination therapy of CF

A

elexacaftor, tezacaftor and ivacaftor

2correctors

43
Q

membrane proteins fold at the ER through the what

A

translocon

44
Q

what other incurable diseases are caused by protein msifolding/aggregation

A

alzeihmers
parkinsons
huntigntons
amyotrophic lateral sclerosis

45
Q

what things help inform new medicine for folding disease

A

computer simulations(predictions can be made on how they fold ) , cell biology and structural studies

46
Q

ACH inhibitors can help Alzheimers true or false ?

A

true

respiratory (22 decks)

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