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Sem 1 - MCBG > Post Translational Processing Of Proteins And Protein Targeting > Flashcards

Post Translational Processing Of Proteins And Protein Targeting Flashcards

1
Q

What are the two main ways that a protein can be processed after translation?

A
  • Proteolytic Cleavage - breaking the peptide bonds to remove parts of the protein.
  • Chemical Modification - adding functional groups to amino acid residues.
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2
Q

How do proteins know where to go in the cell?

A

In 1999, Gunther Blobel won the Nobel Prize for discovering that:
“Proteins have intrinsic sign,as that govern their transport and localisation in the cell.”

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3
Q

What type of ribosomes synthesise proteins destined for the cytosol or post-translational import into organelles?

A

Free ribosomes.

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4
Q

What type of ribosomes synthesise proteins destined for membrane or secretory pathways via co-translational insertion?

A

Ribosomes on the rough endoplasmic reticulum.

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5
Q

What is required for protein sorting?

A
  • a signal (address) intrinsic to the protein,
  • a receptor that recognises the signal and which directs it to the correct membrane,
  • a translocation machinery,
  • energy to transfer the protein to its new place.
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6
Q

How do proteins target peroxisomes? What is the signal intrinsic to the protein?

A

SKL (Serine-lysine-leucine) is the peroxisome targeting sequence that is usually present on the C terminus of the protien.

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7
Q

How do proteins target peroxisomes? What is the receptor that recognised the signal and directs to the the correct membrane?

A

The peroxisome targeting sequence (SKL) is recognised by the recent Pex5 which binds tot he corgi protein in the cytoplasm.

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8
Q

How do proteins target peroxisomes? What is the translocation machinery?

A

13 apex proteins make up a transport channel across the peroxisomal membrane. This binds to the Pex5-cargo complex

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9
Q

How do proteins target peroxisomes? What else is required to allow the recycling of the PTS receptor?

A

ATP hydrolysis is needed to allow recycling of the PTS receptor.

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10
Q

How does the protein get into the persoxisomal matrix?

A
  • In cytosol, the peroxisomal import receptor binds to the cargo with the PTS
  • The peroxisomal protein remains folded and the receptor integrates into the translocon which opens it.
  • The PTS dissociates from the receptor.
  • The receptor is returned to the cytosol (requiring ATP hydrolysis)
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11
Q

What happens if targeting to peroxisomes goes wrong? (what diseases?)

A

You get peroxisome biogenesis disorders. Eg Zellweger syndrome or Rhizomelic Chondrodysplasia Punctata.

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12
Q

What type of proteins can be targeted for secretion?

A
  • Extracellular proteins
  • Membrane proteins
  • Vesicular proteins (eg lysosomes and endosomes)
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13
Q

What name for targeting proteins in the ER/ secretory pathway?

A

Cotranslational transport.

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14
Q

What is retrograde transport?

A

When molecules move away from the axon termini and back towards the cemetery body (move backwards)

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15
Q

What are the two types of secretion form cells?

A
  • Constitutive secretion (when Membrane proteins are constant being made to replace old ones) eg collagen, Immunoglobulins and Albumin
  • Regulated secretion. Eg endocrine cells that secrete hormones like insulin, exocrine cells that secrete digestive juices after feeding and neurocrine cells that secrete neurotransmitter.
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16
Q

What is a signal sequence?

A
  • An N terminal amino acid sequence (always),
  • 5-30 amino acids in length (short),
  • A central region rich in hydrophobic residues,
  • Able to form alpha helixes
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17
Q

What is a signal recognition particle?

A
  • A receptor needed to bind to the signal sequence (peptide) on proteins which are destined for the endoplasmic reticulum,
  • It is composed of 6 proteins and a short piece of RNA
  • It recognises the signal sequence (peptide) and the ribosome.
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18
Q

Summarise the synthesis of secretory proteins and their translocation across the ER membrane.

A

-Free ribosome binds to the signal sequence at the N terminus,
-SRP binds to the signal sequence,
-SRP binds to the SRP receptor in the membrane,
-This causes the translocon to open and the protein to begin going through,
-SRP the unbinds and gets reused (requiring energy),
-A signal peptidase the cleaves off the signal sequence and the protein continues to be synthesised into the ER lumen,
One synthesis has finished, the protein fold in the ER, the ribosome falls off and the translocon closes.

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19
Q

What types of proteins need to be inserted into the ER membrane?

A

Insertion into the ER membrane is required for protein in the ER and for the delivery of proteins destined for the plasma membrane or the internal membrane of the secretory pathway.

20
Q

What is the role of a stop transfer sequence?

A

A stop transfer sequence halts the transfer of peptides across the ER membrane. It acts as an anchor to hold the protein in position.

21
Q

List seven functions of the endoplasmic reticulum.

A
  • Insertion of proteins into membranes
  • Specific proteolytic cleavage
  • Glycosylation
  • Formation of S-S bonds
  • Proper folding of proteins
  • Assembly of multi subunit proteins
  • hydroxylation of selected Lys and Pro residues (Collagen)
22
Q

What is N-linked glycosylation?

A

This is when sugars are added on an asparagine side chain (a reaction involving an amino group -why its N linked-) in the ER

23
Q

Why is glycosylation of proteins important?

A
  • Correct protein folding
  • Protein stability
  • Facilitates interactions with other molecules
  • Deficiencies in N-linked glycosylation leads to severe inherited human disease: Congenital disorders of glycosylation (CDG)
24
Q

What is the role of protein disulphide isomerise (PDI) in the formation if disulphide bonds in the ER lumen?

A

A redox reaction occurs.

The reduces substrate protein (SH) becomes oxidised (S-S) and therefore, PDI gets reduced (from S-S to SH SH)

25
Q

What happens if there are folding problems?

A
  • The Protein may be trapped in a mis-folded conformation.
  • The Protein may contain a mutation which results in misfolding.
  • The Protein may be incorrectly associated with other subunits.
26
Q

What is the role of ER chaperone proteins?

A

The attempt to correct errors in protein folding by:

  • Retaining unfolded proteins in the ER
  • Act as sensors to “monitor” the extent of protein misfolding. Eg they mediate an increase in transcription of chaperones and a decrease in translation.
27
Q

What happens if protein misfolding cannot be corrected?

A
  • Proteins may be retuned to the cytosol for degradation

- Proteins may accumulate to toxic levels in the ER resulting in disease. This may arise due to a single mutation.

28
Q

What is O-linked glycosylation?

A

It is attachment of sugars to the -OH group of serine or threonine in the Golgi. This is important in proteoglycans and is a component of the extracellular matrix and mucus secretions.

29
Q

Describe the processing of preproinsulin

A
  • The signal sequence is removed on entry to the ER (to form just proinsulin)
  • Disulphide bonds are formed between the A and B chains in the ER
  • The C chain gets removed in the Golgi to form insulin. Insulin is made of two separate chains (A and B) joined by disulphide bonds.
30
Q

Why can proteolytic processing yield different products from the same starting material?

A

Because there are different amounts and types of processing enzymes in different cell locations.

31
Q

What is the most abundant protein in the body?

A

Collagen! It is 25-30% of all protein in the body.

32
Q

Where is collagen often found?

A

It is the most abundant fibrous protein in connective tissue so, it is found in Tendons, ligaments, cartilage and bone. It is also present in loose connective tissue to provide structure to internal organs.

33
Q

What is the basic unit of collagen? How are collagen fibres formed?

A

The basic unit it Tropocollagen:

  • 300nm rod-shaped Proteins (Fibrous and not globular),
  • 3 polypeptides (alpha chains), each about 100 amino acids long,
  • Glycine is in every 3rd position along each alpha chain (Gly-X-Y)
  • it forms a characteristic, right handed triple helix
34
Q

State three characteristics of the triple helix structure of collagen

A

Non-extensible
Non-compressible
High tensile strength (stronger than steel)

35
Q

What amino acid is often present in the X or Y positions of Collagen?

A

Proline or hydroxyproline

36
Q

Why do Collagen fibres contain lots of Glycine (Gly-X-Y)?

A

Because Glycine is the only amino acid with a side chain small enough (H) to fit in the middle of the helix.

37
Q

Why do some prolines become hydroxyprolines?

A

This added hydroxyl groups occur so that hydrogen bonds can form between the alpha chains to stabilise the structure. This is for extra strength.

38
Q

What is the role of a signal peptidase?

A

A signal peptidase cleaves off the signal peptide as Collagen enters the ER. This causes preprocollagen to become procollagen.

39
Q

What is the role of Prolyl Hydroxylase?

A

This is the enzyme used to add hydroxyl groups to proline and lysine residues in the procollagen amino acid sequence. These are associated with protien disulphide isomerases (PDI) in the endoplasmic reticulum.

40
Q

What is needed for prolyl hydroxylase to work? What disease occurs if it does not work?

A

Prolyl hydroxylase requires Vitamin C and Iron ions to work. If not then scurvy will occur because this is due to the weak tropocollagen triple helixes (because of the lack of hydrogen bonds)

41
Q

In the synthesis and modification of collagen in the ER, after hydroxylation of proline and lysine, what are the next steps? (6)

A

Glycosylation

  1. The addition of N linked oligosaccharides.
  2. The addition of galactose to hydroxylysine residues.
  3. Chain alignment, formation of disulphide bonds (PDIs)
  4. Formation of triple-helical procollagen from the C- to N-terminus
  5. Completion of O-linked oligosaccharides chains by the addition of glucose (O-linked glycosylation)
  6. Go into a transport vesicle.
42
Q

How is procollagen secreted from the ER and turned into tropocollagen?

A

The vesicle that has formed fuses with the membrane and is secreted by exocytosis.
Then, N- and C-(disulphide linked) terminal propeptides are removed which converts it to tropocollagen. This is now extracellular.

43
Q

How are collagen fibres formed?

A

Collagen fibres are formed outside cells as they are too big to be formed in the fibroblasts where tropocollagen is formed.
After the N and C terminal propeptides have been removed, collagen molecules associate laterally and form covalent cross links. This forms fibrils.
These fibrils then aggregate to form a collagen fibre.

44
Q

What amino acid are the covalent bonds formed between? What is needed for this to work?

A

The covalent bonds / cross links are formed between Lysine residues. These form covalent bonds using Lysyl Oxidase.
This is an extracellular enzyme which requires Vitamin B6 and Copper 2+ ions for activity.

45
Q

What syndrome can be caused if you have a lysyl oxidase deficiency or a mutation in Collagen V?

A

Ehlers-Danilos syndrome (EDS) which results in extra stretchy skin.

Sem 1 - MCBG (16 decks)

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