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Life history of proteins > Lecture 1 compartmentalised cell context > Flashcards

Lecture 1 compartmentalised cell context Flashcards

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1
Q

What are the two locations of ribosomes?

A

Free ribosomes (in cytosol) which are non-compartmentalised and membrane bound ribosomes which are compartmentalised in the ER.

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2
Q

Is protein folding fast or slow?

A

Fast micro seconds to miliseconds.

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3
Q

What does eukaryotic proteins being co-translational mean?

A

Proteins begin to be folded modified or transported as they are still being translated.

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4
Q

What are proteins assisted by?

A

Molecular chaperones.

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5
Q

Why would protein folding be delayed?

A

To assist translocation e.g., ER proteins.

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6
Q

What can happen when protein folding goes wrong?

A

Leads to disease such as prion disease and neurodegenerative diseases.

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7
Q

What is prion disease?

A

fatal neurodegenerative disorders caused by misfolded prion proteins that spread by converting normal proteins into abnormal forms, leading to brain damage, rapid neurological decline, and death, with no cure currently available.

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8
Q

How can proteins be developed?

A

Covalently modified by being acetylated, phosphorylated, glycosylated, lipid anchors added etc.

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9
Q

How can proteins be proteolytically processed?

A

They undergo enzymatic cleavage by proteases to become functional. An essential step to maturation, regulation and activation.

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10
Q

What are examples of proteins being proteolytically processed?

A

Removing signal sequences or the activation of zymogens which are enzymes that can be inactive or active and get activated by cleavage which removes the inhibitory part. Examples are pepsin, trypsin and fibrin.

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11
Q

What are the typical properties of proteins in a eukaryotic cell?

A

Highly compartmentalised, compartments with specialised functions and protein content. Require transport and sorting mechanisms.

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12
Q

How many proteins are there?

A

10^10 with 10^3-4 types.

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13
Q

What is the method of transport to the correct compartment from the cytosol?

A

Gated transport, transmembrane translocation and vesicular transport.

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14
Q

What is the function of the cytosol and cell volume %?

A

Interface with environment, signalling. 54%

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15
Q

What is the function of the rough ER and cell volume %?

A

Membrane and secreted protein synthesis. 9%.

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16
Q

What is the function of the smooth ER and cell volume %?

A

Lipid synthesis 3%.

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17
Q

What is the function of the golgi and cell volume %?

A

Glycosylation. 3

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18
Q

What is the function of the mitochondria and cell volume %?

A

ATP synthesis. 22%.

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19
Q

What is the function of the nucleus and cell volume %?

A

Genome store. 6%.

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20
Q

What is the function of peroxisomes and cell volume %?

A

Oxidative reactions, breakdown of amino acids etc.

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21
Q

What is the function of lysosome and cell volume %?

A

Degradation/ recycling and 1%.

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22
Q

What is the function of the endosomes and cell volume %?

A

Receptor recycling, signaling and nutrition. 1%.

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23
Q

Why is compartmentalisation required?

A

It compensates for a lower surface area to volume ratio giving the proteins more space.

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24
Q

Compare the size of eukaryotic cells to prokaryotic cells.

A

Eukaryotic cells are larger than prokaryotic cells with a lower surface area to volume ratio. Compartments help them to function efficiently.

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25
What is an example of a mechanism that ensures a protein is only active in its correct functional compartment?
The calcium dependent regulation of NF-AT (nuclear factor activated T cells).
26
Explain this calcium dependent NF-AT mechanism.
Calcium levels regulate NF-AT movement between cytoplasm and nucleus. Calcineurin dephosphorylates NF-AT enabling gene transcription in the nucleus. Protein kinases phosphorylate NF-AT keeping it in the cytoplasm. Dysregulation can contribute to inflammation and cancer.
27
What is the regulated method of removing proteins?
Rapid turnover of some proteins by ubiquitin-proteosome system. Triggered by a signal e.g., phosphorylation.
27
What is the constitutive method of removing proteins?
Autophagic-lysosomal system. Slow turnover of proteins.
27
What is protein folding?
Physical process by which polypeptide rapidly/reliably goes from random coil to 3D/functional conformation.
28
What is the importance?
Defects lead neurodegeneration amyloid and allergies. Design of future medicine/novel proteins and technological uses e.g., enzyme to detoxify environment.
28
What is different of protein structure to DNA structure?
Proteins, unlike DNA/RNA are structurally diverse.
28
What were the two approaches to tackling the folding problem?
1. Practical. Unfolding and refolding experiments e.g., Anfinsen 1961. 2. Theoretical. Based on chemical structural and thermodynamic/kinetic parameters e.g., Levinthal.
29
What is the Anfinsen experiment 1?
The RNase A enzyme is unfolded by Beta mercaptoethanol and urea. This reduces disulfide bonds. Results in a fully unfolded, inactive protein. By dialyzing out Beta-ME and urea the protein refolds. RNase A regains enzymatic activity. Demonstrated that protein folding is a spontaneous process driven by thermodynamics.
30
What is the Anfinsen experiment 2?
The beta-ME is removed BEFORE urea is removed. The protein fails to refold properly because S-S reform randomly because the protein is still denatured due to urea. Correct folding requires the proper order of disulfide bond formation.
31
What is the Anfinsen experiment 3?
Adding a small amount of beta-ME partially reduces incorrect disulfide bonds, allowing the protein to slowly refold correctly over time. Shows protein folding is dynamic.
32
What is the conclusion of these three experiments?
Native fold is the most thermodynamically stable (lowest Gibbs free energy). The primary structure has non-covalent interactions that determine the structures, independent of outside forces.
33
What is the levinthal paradox?
Highlights the apparent contradiction between the vast number of possible protein confirmations and the rapid timescale of actual protein folding.
34
What is the maths of the levinthal paradox?
A polypeptide with 100 residues has 99 peptide bonds and 198 different phi and psi angles that define its conformation. Each amino acid can adopt 3 different conformations based on these angles. Total number of possible combinations is an astronomically large number. Proteins fold in 10^-3 to 10^-6 seconds suggesting that proteins do not explore all possible conformations randomly. Suggests they follow specific pathways.
35
What are the different problems of protein folding?
1. Folding processes: kinetics of routes or pathways use to fold so quickly. Difficult to understand how this occurs 2. The folding code: the thermodynamic question balance of interatomic forces for a given amino acid sequence. 3. Predicting a proteins native structure from its amino acid sequence is difficult.
36
What is the hydrophobic collapse?
1. Unfolded state. 2. Secondary structure forms (H-bonds form in micro seconds). Hydrophobic collapse and molten globule formation (dynamic). 3. Native-most thermodynamically stable/lowest free energy.
37
How do local interactions accelerate folding globally?
Protein folding is not random but directed by non covalent interactions between different parts of the polypeptide chain like the backbone and side chain. The native folded state has the lowest free energy and is the most stable. Explains why proteins fold spontaneously under normal biological conditions.
38
What are the 4 early models for folding mechanisms?
Molten globules use hydrophobic collapse. The framework model. The jigsaw model. The nucleation growth model.
39
What is the framework model?
Suggests the local secondary structures such as alpha helices and beta pleated sheets form early during the folding process and then these elements come together to establish the final tertiary structure.
40
What is the nucleation growth model?
Folding begins with the formation of small, partially structures region that contains key interactions critical for the overall structure. Has both secondary and tertiary structures. The rest of the polypeptide condenses around it.
41
What is the jigsaw model of protein folding?
Suggests different segments of the polypeptide chain fold independently and then come together like interlocking puzzle pieces to form the final tertiary structure.
42
What is the energy landscape theory?
The energy landscape includes multiple possible folding pathways. The protein begins in a high energy, unfolded state. The width of the funnel represents the number of possible conformations during folding. Proteins reach their folded state through various intermediate states. The landscape contains energy minima (traps) where proteins can get stuck in partially folded or misfolded states. These require an energy boost from chaperones or incases of incorrect folding it may form oligomers, aggregates, amyloid fibrils.
43
How do ribosomes shape protein folding pathways?
1. Folding begins in the ribosome exit tunnel. The exit tunnel is around 100 angstroms long and 10-20Å wide for 30-40 amino acids. alpha helices begin to form the rest of secondary like beta pleated and tertiary form later. 2. The vestibule (wider region near the tunnels exit) allows more complex structures to form before full exiting. This early folding is influenced by ribosomes shape and interactions with emerging chain. 3. Exit tunnel may change shape to influence folding. Ribosome itself is dynamic. Active involvement in folding. 4. Ribosomes have cofactors to help folding. E.g., ATP for CFTR and Zn2+ for zinc finger proteins. 5. Ribosomes tether emerging chains so they are held in closer proximity increasing local concentration. They contain specific residues and rRNA regions that transiently express correct folding patterns. Protein factors like NAC (nascent polypeptide associated complex) help stabilize early structures to prevent aggregation.
44
What is the relationship between translation speed and folding efficiency?
Folding proceeds from the N-terminus to C-terminus following the order in which amino acids are synthesized. Bacteria translate at 20 amino acids per second whereas eukaryotes translate at 5 amino acids per second. Folding must keep pace with translation to prevent kinetic traps (misfolding that requires unfolding before refolding).
45
What are the methods for studying protein folding?
X-ray crystallography, isotope labelling and mass spectrometry, fluorescence measurements FRET, site directed mutagenesis, NMR, hydrogen exchange, bioinformatics.
46
What is FRET?
Fluorescence resonance energy transfer. A technique to measure the distance between two chromophores, called a donor to acceptor.
47
What does site directed mutagenesis do?
Analyses the effects of mutation on folding kinetics.
48
What does nuclear magnetic resonance NMR measure?
Changes in magnetic resonance occur at around 13C and 15N during refolding.
49
What is hydrogen exchange?
amide hydrogens (hydrogens attaches to the nitrogen atoms of peptide bonds) exchange with the protein deuterium (a heavier isotope of hydrogen) from the surrounding solvent typically heavy water (D2O). In well structure regions such as alpha helix or beta pleated sheet the exchange is slower because these regions are protected from the solvent.
50
What are computational methods of structural prediction approaches for studying protein folding?
Template-based modelling where prediction based on previously determined structure like a related protein. Template free modelling/ab initio folding where novel folds occur and the sequence is used to predict the secondary structure such as backbone angles long-range interactions and conserved residues. Fragment based assembly where 3-15aa fragments are modelled based on similarity with other proteins. Assembled from fragments.
51
What are computational methods for studying protein folding?
Model testing using molecular dynamic simulation. E.g., Rosetta software. AI to predict structure. deepmind or baker lab uni of washington.
52
What are the four computing energy landscapes of protein folding?
Golf course, funnel, coarse-grained energy functions and atomistic functions.
53
What is the golf course landscape?
Represents a flat energy landscape where many different conformations have similar energy levels. Finding the native state requires exhaustive exploration.
54
What is the funnel model energy landscape?
Represents a landscape where most starting points naturally guide towards its native folded state. Model suggests a smoother and more efficient folding process.
55
What is the coarse-grained energy landscape?
Provide a simplified representation of protein folding. Computationally faster but introduce distortions and accuracies.
56
What are atomistic energy functions?
Offer a highly detailed and accurate representation but require significantly more computer power.
57
What are problems of protein folding in vivo?
The cytosol is crowded so inappropriate interactions may occur.
58
What are metamorphic proteins?
A subset of proteins that can form different conformations and adapt different folds such as lymphotactin, viral glycoprotein. They differ from prions as they reversibly switch between different proteins whereas prions have irreversible misfolding.

Life history of proteins (17 decks)

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