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BIOC2001 TEST TWO > Intracellular Protein Trafficking - Dr Bowers > Flashcards

Intracellular Protein Trafficking - Dr Bowers Flashcards

1
Q

Why do specific proteins need to get to specific organelles?

A

Different organelles have specific functions. requiring particular proteins. Each different organelle has different specific proteins that it needs to function

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2
Q

How does a protein know where to go in a cell?

A

Proteins have sorting signals, these are particular sequences coded for int he protein that can direct the protein where to go, they are often at the end of a protein.

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3
Q

What are the two types of sorting signals?

A

Signal sequence - a chain of amino acids usually at the end of a polypeptide chain
Signal patch - Amino acids in the signal are separate until the protein folds

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4
Q

Are signal sequences cleaved or un-cleaved?

A

It depends on the signal sequence, some are cleaved and others are left on.

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5
Q

What is the typical Nuclear import signal?

A

Lysine and arginine - rich sequences

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6
Q

What is the typical Mitochondrial import signal?

A

Amphipathic alpha helix

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7
Q

What is the typical ER import signal?

A

Hydrophobic amino acids

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8
Q

Why cant big proteins cross the lipid bilayer?

A

The lipid Bilayer is hydrophobic and therefore it does not like charged marcomolecules travelling across it

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9
Q

What type of proteins can diffuse through the nuclear pores?

A

Small proteins that are less then 5kd in size

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10
Q

Do larger proteins require active transport to cross the lipid bilayer

A

YES

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11
Q

What three general complexes are required for any protein to cross any bilayer?

A
  • Signal on a protein
  • Receptor protein to recognise the signal
  • Protein channel
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12
Q

Where do all nuclear-encoded proteins begin synthesis?

A

In the cytosol

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13
Q

Is the nuclear membrane a double membrane?

A

Yes

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14
Q

What is a NLS?

A

Nuclear localisation signals - they are strings of positive amino acids, these strings do not need to be at the end of the polypeptide they can be in the middle

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15
Q

Describe the structure of the nuclear pore

A

Nuclear pores are openings in the nuclear membrane filled with lots of proteins. Usually 50-100 different proteins make up a nuclear pore and the proteins are called nucleoporins. A nuclear pore is one of the largest structures in a cell, underneath a nuclear pore there are nuclear baskets.

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16
Q

How do proteins under 5kd in size get into the nucleus?

A

They can freely diffuse through the nuclear pores. Proteins larger then this are imported via active transport.

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17
Q

Describe the process of nuclear import

A

The receptor molecule is a soluble protein called Importin. Importin recognises and binds to the proteins NLS (signal sequence - containing lots of positively charged lysine residues). Once bound to the protein, Importin then binds to FG repeats in the nuclearporins, this then allows the protein to be taken inside the nucleus.
The nuclear import receptor, Importin, is part of the karyopherin family. The nucleoporins (proteins that make up the nuclear pore) have FG repeats that serve as binding sites for the import receptors.

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18
Q

Describe the process of nuclear export

A

The nuclear export receptor molecule is a soluble nuclear protein called Exportin. The export signal sequence on the protein (containing a lot of leucine residues) is recognised by exportin, which then binds to the protein. Again the nuclear export receptor is part of the karyopherin family. Exportin then interacts with the FG repeats on the nuclear porins and this takes the protein out of the nucleus. Nucleoporins have binding sites for export receptors as well.

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19
Q

How does importin get back into the cytosol?

A

Once inside the nucleus, Ran-GTP binds to the importin receptor and displaces the protein molecule. The protein is now free in the nucleus. The Ran-GTP bound to the importin takes the importin back out into the cytosol. Once in the cytosol the Ran-GTP is converted into Ran-GDP via an enzyme, this transformation releases the importin back into the cytosol and thus replenishing the receptor.

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20
Q

How does Ran-GDP get back into the nucleus?

A

After displacing importin, the Ran-GDP returns to the nucleus via its own nuclear importer called NGF2.

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21
Q

What is the relative concentrations of Ran-GTP and Ran-GDP in the cytosol and nucleus?

A 
Cytosol: 
Ran-GTP - LOW 
Ran-GDP - HIGH
Nucleus:
Ran-GTP - HIGH
Ran-GDP - LOW
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22
Q

How does Exportin interact with Ran-GTP?

A

Exportin binds to the protein that is to be exported. Ran-GTP then also binds to make a triple complex. This triple complex is then taken out of the nucleus via interactions between exportin and the FG repeats on the nucleoporins. Once in the cytosol the Ran-GTP dissociates from the complex and is converted into Ran-GDP by an enzyme. The exportin then dissociates and the protein is free in the cytosol. The exportin is then transported back into the nucleus via the nuclear pore.

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23
Q

Nuclear import and export is post-translational, what does this mean?

A

The protein is fully folded when it is transferred across the membrane

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24
Q

Describe a mitochondrion protein signalling sequence

A

An amphiphatic alpha helix, an example being cytochrome oxidase, subunit IV. There are positively charged residues on one side of the helix and negatively charged residues on the other. These signals are usually at the extreme N terminus of a polypeptide but not always.

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25
Q

Where do proteins that cross the mitochondrial double membrane cross and why?

A

The mitochondria have a double membrane to maximise the surface area for the electron transport chain to occur. Proteins that cross the mitochondrial membrane do so at locations where the inner and outer membranes are very close together, to minimise the distance that they have to travel though the membrane

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26
Q

Why are so many of the mitochondrial proteins imported?

A

The mitochondrial genome only encodes for 13 proteins, so the remaining 99% of the proteins it needs to function are nuclear encoded and translated in the cytosol and therefore need to be imported.

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27
Q

Describe the mitochondrial import of a protein

A

The amphiphatic signal sequence is recognised by a receptor molecule that is membrane bound. The membrane bound receptor is part of a complex of proteins called the TOM (translocon of outer membrane) complex. This complex makes a channel across the outer membrane of the mitochondria. Once the receptor recognises the signal on the protein it allows it to travel through the TOM complex. The signal sequence is then recognised by the TIM complex and the protein is allowed through the inner membrane. Once insdie the mitochondria the signal sequence can be cleaved and the protein folds up.

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28
Q

Are proteins folded during mitochondrial import?

A

No, proteins cannot travel into the mitochondria in a folded state, therefore the protein remains unfolded until it is inside of the mitochondria.

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29
Q

How is a mitochondrial protein kept it its unfolded state as it travels into the mitochondria?

A

The protein to be translocated is kept unfolded by the binding of cytosolic Hsp70. Hsp70 is an ATPase that continually hydrolyses ATP to keep the protein in the unfolded state. once in the inter-membrane space it is the membrane potential that keeps the protein unfolded. Whilst travelling through the TIM complex a Hsp70 molecule inside of the mitochondria binds to the end of the polypeptide. This Hsp70 pulls the protein through the TIM into the mitochondria and prevents it from backsliding by hydrolysing ATP. Once inside the mitochondria the protein Hsp60 helps the translocated protein fold correctly, this also uses ATP.

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30
Q

Name the three ways that ATP is hydrolysed un mitochondrial import

A

Hsp70 - to keep the protein unfolded
Hsp60 - to fold the protein once inside the mitochondria
And to establish a membrane potential to keep the protein unfolded in the inter-membrane space.

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31
Q

Describe how mitochondrial membrane proteins in general become imbedded in the outer membrane

A

The protein travels across the TOM in the normal way, once the protein is in the inter-membrane space chaperones bind to it to prevent it from folding. The unfolded protein is then triggered to start travelling through a stem complex back into the cytosol. However the hydrophobic region of the polypeptide is attracted to the inside of the bilayer and remains stuck in the stem. Then the protein folds into its native structure on the outer mitochondrial membrane.

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32
Q

Describe the four examples of how a protein can become imbedded in the inner mitochondrial membrane.

A
  • cleaving of the signal sequence whilst travelling through the TIM, leaving the hydrophobic region in the inner membrane and the rest of the protein in the inter-membrane space
  • Cleaving of a signal sequence could unmask another signal sequence which can then be recognised by the OXA complex and bind here, making another inner mitochondrial protein.
  • After travelling trough TOM the unfolded protein can bind to a complex called TIM22 and this can cause the protein to fold and become an inner membrane protein
  • Whilst traveling through TIM the signal sequence is cleaved by a protease and this releases the protein into the inter-membrane space and it can fold there and become a soluble protein.
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33
Q

What is the definition of Translocation?

A

Change of location, in the context of protein trafficking, translocation refers to a protein crossing a membrane

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34
Q

What is the definition of Nascent?

A

Nascent means coming into being. A nascent chain is therefore a newly synthesised polypeptide chain

35
Q

What is the definition of Glycosylation?

A

Refers to the addition of sugars to protein or lipid

36
Q

What is a typical example of an ER signal sequence?

A

Charged residues followed by lots of hydrophobic residues, this sequence usually occurs at the N terminus of the polypeptide. It is a prelysozyme, the sequence has 1 or more charged amino acids followed by a stretch of 6-12 hydrophobic amino acids

37
Q

What is the first part of a protein that is translated?

A

The N terminus

38
Q

Protein import into the ER is mostly co-translational, what does this mean?

A

That the protein is not fully synthesised as it is translocated into the ER.

39
Q

Describe ER protein import

A

SRP (Signal recognition particle) is made up of both RNA and protein. SRP binds to the signal sequence (the first part to be translated) of the nascent chain, the nascent chain bound SRP then binds to the SRP receptor on the ER membrane. The nascent chain is then targeted to the translocon complex (called Sec61), the protein travels through Sec61 and into the ER.

40
Q

What is special about SRP binding?

A

The binding causes a pause in the translation of the protein. The SRP pulls the nascent chain and the attached ribosome to the SRP receptor on the ER membrane. The nascent chain and attached ribosome is then passed to the translocon complex Sec61, this transfer is mediated by the SRP receptor. The SRP molecule dissociates. Now translation continues and the chain is being translated straight across the ER membrane and into the ER. If the protein is anER soluble protein it is translated into the lumen, if it is a membrane bound protein it is translated into the ER membrane where it stays. This process is powered by GTP hydrolysis.

41
Q

What does GTP hydrolysis power in ER translocation?

A

Assembly of the nascent chain - translocon complex and the release of the SRP - SRP receptor.

42
Q

Describe translocation into the ER of a protein that does it post-translationally

A

The fully synthesised protein is kept unfolded by the molecule Hsp70. The protein is passed through the Sec61 complex with the help of proteins Sec62/63/71 and 72, which recognise the signalling sequence of the protein. The protein BiP hydrolyses ATP to prevent the protein from slipping back through the Sec61 complex, it also pulls the protein into the ER.

43
Q

Describe the translocation of a soluble protein into the ER lumen

A

An unfolded soluble ER protein in the cytosol binds to an inactive translocator (such as Sec61?) via its signalling sequence. This activates the translocator and the protein is taken across the membrane, a signal peptidase is then recruited and this cleaves off the signal sequence and the mature soluble protein is free in the ER lumen.

44
Q

Describe the translocation of a membrane protein into the ER membrane

A

The membrane protein will have regions of hydrophobic areas that would prefer to be imbedded in the membrane. The signal sequence on the protein recognises a translocator protein (Sec61?) and the polypeptide travels through. The signal sequence that is still attached to the translocator is then cleaved and left in the membrane. The next hydrophobic region in the polypeptide will stay in the membrane as it travels trough as it is energetically favourable. This then becomes the membrane domain.

45
Q

Whats the difference between a type 1 membrane protein and a type 2 membrane protein?

A

In type 1 membrane proteins the C terminus is in the cytosol and the N terminus is in the ER.
In a type 2 membrane protein the C terminus is in the ER and the N terminus is in the cytosol

46
Q

Where does core glycosylation occur?

A

In the ER on asparagine residues. The sugar groups comes from a lipid-linked oligosaccharide, The enzyme oligosaccharyl transferase allows the sugar to leave the oligosaccharide and be added to the ASN on the polypeptide chain that is translocating from the cytosol.

47
Q

What is the role of chaperones inside the ER?

A

Helping the protein fold correctly and mark incorrectly folded proteins for degradation

48
Q

What are disulphide bonds and why are they only formed in the ER?

A

Disulphide bonds are covalent links between two cysteine residues that help stabilise the tertiary and quaternary structure of a protein It is the oxidising environment inside the ER that allows disulphide bonds to be formed.

49
Q

What is ERAD?

A

ER- associated degradation, it is the process of degrading missfolded proteins from the ER. Missfolded proteins are taken back out of the ER, usually by the Sec61 translocon. Once in the cytosol the sugars are cleaved and ubiquitin is added and then polyubiquitination occurs where lots of ubiquitins are added. This targets the protein for degradation in the proteasome, which is a cytosolic machine that degrades proteins.

50
Q

Describe the transfection approach to studying translocation across membranes

A

A specific sequence that is suspected to be a signal sequence is added to the GFP gene, you can then see where the signal goes as the GFP glows. Anti-calnexin can be used to stain organelles in the cell such as ER so that GFP would be easier to see

51
Q

Describe the Biochemical approach to studying translocation across membranes

A

Fractionate the organelles and see if a particular organelle has more of one type of protein then the other organelles, this protein must be targeted to that organelle then.

52
Q

Describe the Genetic approach to studying translocation across membranes

A

In the Genetic approach, yeast is used widely as a model organism in protein trafficking studies. Sequence screens have been used to identify components of the translocation pathways such as Sec61. In the Genetic approach you are trying to knock out a gene and see what implications this has on translocation. This is easier to do in yeast as it is a haploid with only one set of genes, whereas most cells are diploid

53
Q

Why is the ER a special place to be translocated to?

A

Because the ER is the starting place for proteins that are destined for many different locations, in the ER they are glycosylated and folded.

54
Q

What are proteins that remain in the ER called? give an example

A

Proteins that remain in the ER are called resident proteins, an example being BiP.

55
Q

If a signal sequence that got a protein into the ER is cleaved off then how does the ER know where to send the protein?

A

Though the signals that got the protein to the ER may have been cleaved off, there are still other signals that get the protein to the correct place after this. There are many different types of these signals and some proteins have more then one signal

56
Q

Signals that direct proteins to the correct place can be two types once in the ER, what are they?

A
  • Amino acid sequences such as signal sequences or signal patches
  • Protein modification such as glycosylation, ubiquitination and lipid modifications
57
Q

Name the two ways that a protein can be transported from one membrane bound compartment to another?

A

Vesicular transport

Direct Fushion

58
Q

Describe vesicular transport

A

A protein is included in a vesicle that buds off and then is fused with another compartment.

59
Q

What allows a transport vesicle to form and select what protein is incorporated inside?

A

The electron dense vesicle coat. Different types of coats sort proteins at different transport steps. The different coats are made up of different protein and they make the compartmental membrane deform and form a bud, they also select which protein is going to be incorporated into the vesicle.

60
Q

What are the three types of transport vesicle?

A

COPII
COPI
Clathrin with associated accessory protein

61
Q

Describe the general mechanism of a protein being transported via vesicular transport

A

The target protein binds to its specific receptor and both are incorporated into the vesicular structure . A GTP binding protein is also incorporated in the vesicle structure and this is involved in the assembly of the protein coat. GTPases ARF and Sar1 (COPII) control coat recruitment. These GTPases also control the disassembly of COPI and COPII coated vesicles. Clathrin requires Hsp70 family ATPase.

62
Q

What is the role of V/T-SNARE proteins?

A

They are required for fusion once the vesicle is uncoated.

63
Q

What is direct fusion?

A

Direct fusion is when two compartments fuse to form a hybrid organelle, for example a late endosome and a lysosome fuse together in this manner to create a hybrid organelle. The endosome contains the proteins that need to be degraded and the lysosome contains the digestive enzymes, when they fuse this allows the digestion to occur.

64
Q

Describe the assembly of a coated transport vesicle (clathrin)

A

Upon ligand (protein to be transported) binding to the receptor on the membrane, an adaptor molecule AP2 binds, AP2 binds to a specific region on the receptor and helps with the recruitment of more proteins. Clathrin binds to the AP2 molecule and begins to form a cage-like structure. The vesicle is unable to break off until a GTPase is also incorporated. The GTPase is required for the vesicle to break off. Once free in the cytosol the vesicle looses its clathrin coat and AP2 adaptors, and you end up with a naked transport vesicle.

65
Q

Describe the disassembly if the transport vesicle.

A

Once the vesicle is uncoated it needs to fuse to the target membrane and the vesicle has to ensure that it fuses with the correct membrane. There are t-SNARE proteins on the target membrane and v-SNARE proteins on the vesicle. Specific t and v-SNARES are compatible and this ensures that the vesicle fuses with the correct membrane.
Every SNARE interaction involves 4 alpha helices, 3 are t-SNAREs and 1 is the v-SNARE. The interaction is called the trans-SNARE interaction complex. All the 4 SNARES will end up in the same bundle on a membrane.
A Rab-GTP molecule is on the outside of the vesicle membrane and its binds to a tethering protein on the target membrane called the Rab effector. This brings the vesicle and the target membrane closer so that the SNARES can interact. If the SNARE interaction is correct the vesicle is pulled to the membrane and fuses, releasing its contents into the new compartment.

66
Q

What is the cis-SNARE complex and how is it broken up?

A

The cis-SNARE complex is the complex formed when the 4 alpha helices of the SNARES involved in the disassembly of the transport vesicle clump together in a bundle. ATPase NSF and associated protein alpha SNAP binds to the cis-SNARE complex and breaks it into its original parts so that they can be used again.

67
Q

Describe how soluble ER resident proteins are maintained in the ER

A

ER resident proteins are usually proteins involved in glycosylation. The proteins are not physically restrained in the ER they remain due to concentration. Vesicles are constantly budding off from ER and they accidentally take some of the resident proteins with them. COPII vesicles take them back to the Golgi. In the Golgi the ER resident proteins are recognised and taken back into the ER. In all ER resident proteins there is a KDEL signal at there C terminus, a KDEL receptor in the cis-Golgi (also brought form the ER in the COPII) recognises the resident protein and binds to it. KDEL receptor then interacts with the COPI coat and this brings the resident protein back to the ER along with the KDEL receptor inside a COPI vesicle.

68
Q

Why do soluble ER resident proteins bind to the KDEL receptors in the cis-Golgi but dissociate in the ER?

A

The cis-golgi is slightly more acidic then the ER and this allows the binding of the KDEL sequence on the resident protein to the KDEL receptor. When it is back in the ER at a higher pH then dissociation occurs to release the resident protein as it is more alkaline.

69
Q

Describe how transmembrane ER resident proteins are maintained in the ER

A

The mechanism is very similar to the soluble protein mechanism but the retrieval signal is KKXX and it occurs on the C terminus of the transmembrane protein. The two amino acids in the sequence are lysine’s and the next two can be any amino acids. It is membrane bound and so it is taken into the COPI/II vesicles by being part of the membrane that buds off. It is incorporated into the associated vesicles due to its retrieval signal.

70
Q

Describe the process of exocytosis

A

The protein to be secreted starts either on the ER membrane or in the lumen, if it starts on the membrane then the first step is for it to travel to the lumen. The protein is then incorporated into COPII vesicles and travels to the cis-Golgi, where it travels through the Golgi, ending up at the trans-Golgi. From the trans-Golgi there is a special type of vesicle budding off called constitutive secretion and this is unregulated.
Some specialised pathways however do regulate tis process. Specialised secretory vesicles are produced and held in the cell until they receive a signal from the outside and they they fuse with the plasma membrane and release the target protein into the bloodstream.

71
Q

What happens to a protein that is going to be secreted as it travels through the Golgi?

A

In the ER proteins are glycosylated via N-linked glycosylation, whilst travelling through the Golgi there are enzymes that recognise these sugars and add different properties to the protein. By looking at how much modification a protein has had, this is a good way to tell you how far the protein has travelled through the Golgi. Once a protein moves to a certain point through the Golgi it becomes Endo-H-resistant, this means that its sugars cannot be trimmed.

72
Q

What is O-linked glycosylation?

A

Sugars are added to the -OH groups of Serine or Threonine, this reaction is catalysed by a series of glycosyl transferase enzymes in the Golgi

73
Q

What are the two models as to how proteins travel through the Golgi?

A

Vesicular transport model

Cisternal maturation model

74
Q

Describe the vesicular transport model

A

Vesicles bud off one stack and fuse to the next stack, this can work in both the forward and backward direction. This is not the favoured model

75
Q

Describe the Cisternal maturation model

A

Each stack is called a Cisternae and each one will gradually mature into the next cisternae in the sequence, for example a cis stack will mature into a trans stack etc. To balance this out there is reverse vesicular transport, a trans Golgi has to send all the enzymes that make it a trans Golgi back to the previous stack in vesicles. The stack behind will become the new trans stack and the original trans will receive enzymes in a vesicle from the stack in front of it and also mature.

76
Q

Describe a lysosome

A

They contain proteases and lipases for degrading proteins and lipids
They can be considered concentrated bags of enzymes
Fuses directly with the late endosome to create a hybrid organelle and is then reformed
The lumen is acidic with sometimes a pH as low as 5

77
Q

Describe how a soluble lysosomal resident protein gets into a lysosome?

A

A lysosome destined enzyme that is travelling through the Golgi will be phosphorylated with mannose 6 phosphate in the cis-Golgi. This is then recognised by the M6P receptor which binds to the protein and both are incorporated into a vesicle, this is receptor dependent transport. The vesicle then fuses with the late endosome which is very acidic, this acidity causes the lysosome enzyme to dissociate from the receptor. The lyosome protein then waits until the late endosome fuses with the lysosome, and thats how it gains entry.

78
Q

What causes I cell disease?

A

If mannose 6 phosphate is not added to the lysosome enzyme in the cis-Golgi then the enzyme is secreted out of the cell. Patients with this disease rarely live over the age of 10.

79
Q

Describe the process of endocytosis of the LDL receptor

A

LDL stands for low density lipoproteins, a type of cholesterol in the blood stream. This is how the cells take up cholesterol. LDL binds to the LDL receptor on the the plasma membrane, it gets taken in via a coated vesicle. Once inside the cell the vesicle is uncoated and fuses with an early endosome, the early endosome has a slightly lower pH and this allows the LDL to dissociate from its receptor. The LDL receptor is then returned to the plasma membrane via a vesicle. When the late endosome fuses with the lysosome the LDL will be broken down to release free cholesterol into the cell.

80
Q

What is the signal for endocytosis?

A

A Tyrosine based signal YXX0 (0 means anything hydrophobic can be in the 4th region) is an endocytosis signal.

81
Q

How was the LDL receptor endocytosis signal discovered?

A

Joseph Goldstein and michael brown were studying patients with familial hypercholesterolemia
One patient had an amino acid change - NPVY to - NPVC - in the cytoplasmic domain of the LDL receptor
LDL still binds to the mutant receptor but it fails to internalise
LDL can not be cleared from the blood

82
Q

Describe the process of endocytosis of the EFG receptor

A 
EGF receptor (EGFR) on the plasma membrane binds to EGF. The binding occurs at the same time as dimerisation of the receptor, and therefore two molecules of EGF (ligand) bind. This triggers endocytosis and again the signal is tyrosine based, this type of signal is a very common endocytosis signal. 
A small ubiquitin protein is added and this marks it for degradation. The vesicle containing the EGF/EGFR fuses with an early endosome inside of the cell. Once it has fused the EGF does not dissociate from the receptor. The ubiquitin signal was added using the signal FYRAL, is recognised by the late endosome and this directs the EGFR to travel into the internal part of the endosome where it fuses with the lysosome and is degraded.
83
Q

Why does the EGFR signal need to be digested by the lysosome?

A

When EGF binds to the EGFR this tells the cell to proliferate. Therefore, it is important that the signal is switched off so that you do not get over proliferation of the cell. It is in the cytosol that the protein for the signal cascade for cell proliferation occurs. So once the EGFR is taken into the internal parts of the endosome then the signal cascade is stopped and no more cell proliferation should occur. Just to be sure that no more cascading occurs the EGFR is also degraded by the lysosome.

84
Q

Protein trafficking pathways are saturable, what does this mean and how does it affect studies into protein trafficking?

A

You can study a particular protein or signalling sequence by adding GFP to it and seeing where it travels. If you over-express your protein of interest too much though then you can saturate the pathways and therefore you might see proteins in locations that you would not normally.

BIOC2001 TEST TWO (9 decks)

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