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MGD > Session 6 > Flashcards

Session 6 Flashcards

0
Q

When do ribosomes remain cytosolic?

A
  • Protein is destined for cytosolic or posttranslational import into organelles
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1
Q

When do ribosomes attach to the ER membrane?

A
  • Protein is destined for membrane or secretory pathway via co-translational insertion
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2
Q

What is required for protein sorting?

A
  • Signal intrinsic to the protein
  • Receptor that recognises the signal and directs it to the correct membrane
  • Translocation mechanism
  • Energy to transfer the protein to a new place
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3
Q

Describe the constitutive secretory pathway

A
  • Continuous process
  • Proteins packaged into vesicles and released continuously by exocytosis
  • eg serum albumin, collagen
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4
Q

Describe the regulated secretory pathway

A
  • Proteins release in response to a signal eg hormone

- Proteins packaged into vesicles but not released until stimulus is received eg insulin

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5
Q

Describe protein synthesis in the secretory pathway

A
  • Free ribosome initiates protein synthesis from mRNA molecule
  • Hydrophobic N-terminal signal sequence is produced
  • Signal sequence of newly formed protein is recognised and bound by the signal recognition particle (SRP)
  • Protein synthesis stops
  • GTP-bound SRP directs the ribosome synthesising the secretory protein to SRP receptors on the cytosolic face of the ER
  • SRP dissociates
  • Protein synthesis continues and the newly formed polypeptide is fed into the ER via a pore in the membrane (peptide translocation complex)
  • Signal sequence is removed by a signal peptidase once the entire protein has been synthesised
  • The ribosome dissociates and is recycled
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6
Q

What protein modifications can take place in the ER?

A
  • Signal cleavage (signal peptidase)
  • Disulphide bond formation (protein disulphide isomerase)
  • N-linked glycosylation (oligosaccaride-protein transferase)
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7
Q

What protein modifications can take place in the Golgi?

A
  • O-linked glycosylation (glycosyl transferase)
  • Trimming and modification of N-linked oligosaccarides
  • Further proteolytic processing (some proteins only)
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8
Q

What is N-linked glycosylation?

A
  • Oligosaccaride is built up on a Dolichol Phosphate carrier molecule that sits in the membrane
  • Dolichol Phosphate is a special long chain hydrocarbon molecule that inserts into the membrane with its phosphate group protruding
  • The oligosaccaride is transferred to the amide group of Asparagine (Asn) via a N-glycosyl link
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9
Q

What is O-linked glycosylation?

A
  • The modification of the Hyroxyl groups of serine and threonine
  • Glycosyl transferase builds up a sugar chain from nucleotide sugar substrates
  • Carbohydrate added via glycosidic link to hydroxyl of Serine or threonine
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10
Q

What role does proteolytic processing have in the formation of secreted proteins?

A
  • Exoproteases (eg amino peptidase, carboxypeptidase) are used
  • Removal of the pre-segment takes place in the ER and involves the proteolytic removal of the N-terminal signal sequence
  • Removal of the pro-segment occurs in some proteins and takes place in the Golgi
  • eg preproalbumin -> proalbumin -> albumin
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11
Q

How is the mature insulin molecule formed?

A
  • Preproinsulin contains a signal sequence, and A, B and C peptides
  • The signal sequence is cleaved by the signal peptidase enzyme leaving proinsulin
  • Proinsulin contains A, B and C peptides
  • Endopeptidases cleave C peptide leaving insulin (active form)
  • Insulin contains A and B peptides joined by disulphide bridges
  • C peptide is a good marker for measuring levels of endogenous insulin in diabetes
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12
Q

What is the basic unit of collagen?

A
  • Tropocollagen
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13
Q

What is the primary sequence of collagen?

A
  • Glycine-X-Y

- Mostly Proline or Hydroxyproline in X and Y positions

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14
Q

What is collagen made up of?

A
  • 3 polypeptides: 3 a-chains in a left handed triple helix (non-extensible/compressible, high tensile strength)
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15
Q

What is the function of Proline residues in collagen?

A
  • Give correct geometry for extended a-chain conformation

- Prevents the peptide assuming another shape eg a-helix, B-sheet

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16
Q

What is the function of Hydroxyproline residues in collagen?

A
  • Increases amount of inter-chain H-bonds
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17
Q

How is Hydroxyproline formed?

A
  • From Proline residues by the enzyme Prolyl Hydroxylase
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18
Q

What does Prolyl Hyrdroxylase need and why is it important?

A
  • Requires Vitamin C and Fe2+ for activity

- Scurvy is due to low Vitamin C as there is weak tropocollagen triple helices

19
Q

How are Tropocollagen subunits synthesised?

A
  • Synthesised first as preprocollagen (pre-hydrophobic signal sequence marks protein for secretion; pro-subunits synthesised with N- and C-terminal peptides to prevent the formation of collagen fibres inside cells)
  • Procollagen is secreted from cells by exocytosis
  • Procollagen Peptidases cleave N and C terminal peptides (extracellular)
  • Collagen subunits (Tropocollagen) form covalent cross-links
    ~Lysine residues -> aldehyde derivates by enzyme lysyl oxidase (requires vitamin B6 and Cu2+ ions)
    ~ Aldehyde derivates then spontaneously form Aldol cross-links
20
Q

Where do the proteins in the nucleus come from?

A
  • Made on ribosomes in the cytoplasm and are transported into the nucleus
21
Q

How do proteins from the cytoplasm enter the nucleus?

A
  • Proteins pass through nuclear pores (protein channels that span nuclear membrane)
  • Proteins that need to enter the nucleus contain a Nuclear Localising Sequence (NLS) (4-8 basic amino acids in primary sequence)
  • Needs proteins to shuttle between cytosol and nucleus (eg importin) to import nuclear proteins
22
Q

What is the process of importing nuclear proteins from the cytosol into the nucleus?

A
  • Fully folded protein with a NLS is bound by importin a and B in the cytosol
  • Resulting complex binds to the nuclear pore and translocation unto the nucleus in an energy dependent mechanism
  • Once inside the nucleus, the nuclear protein is released and the importins bind to a small GTPase protein know as Ran
  • Importins are exported from the nucleus and can recycled to transport more nuclear proteins
  • Ran is transported back to the nucleus following hydrolysis of GTPASE
23
Q

Where are mitochondrial proteins synthesised?

A
  • In the cytosol
24
Q

In what state are mitochondrial proteins transported into the mitochondria?

A
  • Unfolded state
25
Q

What do proteins destined for the mitochondria contain?

A
  • Amphipathic N-terminal signal sequence of 10-80 amino acids
26
Q

What are the unfolded mitochondrial proteins stabilised by in the cytosol?

A
  • Interaction with molecular chaperones such as Mitochondrial Import Stimulating Factor (MSF)
27
Q

What recognises the signal sequence of mitochondrial proteins?

A
  • Recognised by TOM proteins in the outer membrane that form a protein import channel (Translocase of the Outer Membrane)
  • Proteins destined for the matrix are transported across the inner mitochondrial membrane by TIM proteins (Translocase of the Inner Membrane) (requires ATP and a membrane potential)
  • Proteins of the inner mitochondrial membrane also contain additional signals that stop them entering the matrix
28
Q

What happens to the protein once across the inner mitochondrial membrane?

A
  • N-terminal sequence is removed by mitochondrial processing peptidase (MPP)
  • The protein folds into its native conformation in an ATP-dependent process helped by chaperones eg mitochondrial Hsp70
29
Q

How are lysosomal hydrolases targeted to lysosomes?

A
  • Addition of Mannose-6-phosphate (M6P) signal to N-linked oligosaccarides on the protein
  • Occurs in the Golgi
  • Involves enzymes: N-acetylglucosamine phosphotransferase;
    N-acetylglucosamine phosphoglycosidase
30
Q

How are proteins destined for lysosomes targeted for the addition of the M6P groups

A
  • Presence of a signal patch (sequence of several amino acids from different parts of the amino acid sequence)
31
Q

What are M6P groups on the targeted proteins recognised by?

What happens to the receptors?

A
  • M6P receptors at the trans Golgi
  • Vesicles are pinched off for transport to the lysosome
  • Once at the lysosome, the acid pH causes dissociation of the protein and receptor
  • The receptor is recycled back to the Golgi for further use
32
Q

How is the protein prevented from returning to the Golgi with the receptor from the lysosome?

A
  • Phosphate group is removed from the M6P group on the protein
33
Q

What is I-Cell disease and what is it caused by?

A
  • Genetic defects in the N-acetylglucosamine phosphotransferase enzyme result in a lack of M6P addition to lysosomal targeted proteins
  • In I-cell disease this results in lysosomal hydrolases being mistargeted for secretion -> large amount of these proteins present in the blood and urine
34
Q

What proteins and how can they be lost from the ER?

A
  • Proteins like protein disulphide isomerase and signal peptidase that are resident within the lumen of the ER
  • Lost when vesicles are pinched off and transported to the Golgi
34
Q

What happens to lost proteins?

A
  • There is a selective method that allows ER-resident proteins that have escaped to be retrieved
35
Q

What is the selective method of retrieval of ER proteins?

A
  • ER resident proteins have the sequence Lys-Asp-Glu-Leu (KDEL) near the C-terminus
  • These interact with KDEL receptors in the Golgi (enhanced by low pH)
  • ER proteins bound to the receptor are returned to the ER in transport vesicles
  • ER resident proteins dissociate from the receptor in the neutral condition within the ER
  • KDEL receptor is transported back to the Golgi
36
Q

What drug targets bacterial cell walls and how?

A
  • Penicillin
  • Inhibits transpeptidase enzyme that forms cross-links in the cell wall
  • Osmotic pressure causes cell lysis
37
Q

What drug affects bacterial transcription and how?

A
  • Rifampicin

- Binds to bacterial RNA polymerase preventing transcription

38
Q

What drug affects bacterial protein synthesis and how?

A
  • Tetracycline

- Competes with tRNA at A site of bacterial ribosome

39
Q

What drugs act as anti-folates in cancer therapy and how?

A
  • Methotrexate
  • Impairs synthesis of tetrahydrofolate (which is essential for DNA synthesis) from folic acid
  • Competitively inhibits dihydrofolate reductase (DHFR)
40
Q

What general mechanisms can cause cells to become resistant to an an antibiotic or drug?

A
  • High rate of division
  • Decreased influx
  • Increased efflux
  • Increased transcription of target
  • Altered target
41
Q

How does a high rate of division cause resistance in cells?

A
  • Causes a higher rate of mutation in bacteria in cancer cells
  • Positive mutations (eg drug resistance) will be positively selected for and breed a population of drug resistant cells
42
Q

How does a decreased influx cause resistance in cells?

A
  • Drugs that require to be taken up by their target cells to have an effect can have their influx reduced (eg rifampicin, tetracycline, methotrexate)
  • Cells express a reduced or altered amount version that reduces the affinity of the carrier protein that allows the drug through the cell membrane
42
Q

How does increased efflux cause resistance in cells?

A
  • P-Glycoprotein (Multi-Drug Resistance Protein 1 (MDR1) - similar in structure to CFTR a) is responsible for the efflux of toxic products from a cell
  • Expression of P-Glycoprotein is up-regulated in many cancers, allowing the cells to increase the efflux of chemotherapy drugs eg Methotrexate
44
Q

How does increased transcription of target cause resistance in cells?

A
  • Increasing the transcription of the target product, eg ribosome or enzyme, can overwhelm the drug
46
Q

How can an altered target cause resistance in cells?

A
  • If the target acquires a mutation, the affinity of the drug for it is reduced

MGD (9 decks)

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