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Molecular Cell Biology > Lecture #6 > Flashcards

Lecture #6 Flashcards

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AP® Biology flashcards
1
Q

protein synthesizes found in what three intracellular compartments?

A

cytosol, ER, and mitochondria

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2
Q

what is the definition of folding?

A

reaching the correct tridimensional native structure

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3
Q

in its native structure, how many bonds does RNAse have?

A

4

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4
Q

what is the Levinthal paradox?

A

protein folding does not occur by chance → you can form mathematical calculations for 10^27 years to try to find all combinations for 1000 aa

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5
Q

what type of process is protein folding?

A

thermodynamic

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6
Q

when are proteins in their most stable conformation with the lowest energy?

A

in their native conformation

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7
Q

describe the misfolded conformation:

A

when they are not folded in the right way, but are more stable in respect to the folded ones

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8
Q

what forces drive protein folding?

A
  • hydrophobic interactions
  • electrostatic interactions
  • hydrogen bonds
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9
Q

what are chaperones?

A

proteins themselves that are involved in assisting the folding of other proteins - they are present in all compartments where folding occurs

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10
Q

what are molecular chaperones?

A

heat shock proteins

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11
Q

what is the entry site of the secretory pathway?

A

ER

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12
Q

how is the ER involved in the secretory pathway?

A

it is the site in the cell where all the proteins that have to be secreted and have to be exposed to the pm are located and where all the enzymes that work into the secretory pathway are synthesized

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13
Q

what are the different covalent modifications of the ER?

A
  • cleavage of the leader peptide
  • N-glycosylation
  • GPI anchors
  • SS bond formation
  • Hydroxylation (pro and lys)
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14
Q

why do we need specific enzymes or chaperones the that help protein folding in the ER?

A

the ER is a crowded environment and has a high protein concentration → environment where lots of proteins are folding at once

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15
Q

what are private chaperones?

A

chaperones that are used by specific proteins that are more difficult to fold

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16
Q

What is the most famous chaperone in the ER?

A

BiP

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17
Q

what is BiP?

A

immunoglobin binding protein →Hsp 70 - most abundant chaperone in all cells

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18
Q

what types of domains does BiP have?

A

an ATPase domain and stubstrate-binding domain

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19
Q

what region of the protein is BiP able to bind?

A

able to bind the exposed hydrophobic regions of the proteins trying to fold

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20
Q

what happens to proteins after BiP binds to their hydrophobic regions?

A

the hydrophobic regions of soluble proteins are going inside, so a protein that is trying to fold still exposes its hydrophobic regions, BiP can recognize the parts and bind to them helping the folding using ATP hydrolysis preventing aggregation between unfold proteins

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21
Q

under what condition is BiP the most up-regulated protein?

A

stress conditions

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22
Q

what is N-Glycosylation?

A

the addition of the sugar on the lateral residue of Asparagin (-NH2) OR to those have have the sequence Asn-X-Ser/Thr (X stands for every amino acid besides proline)

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23
Q

on what proteins does N-Glycosylation occur?

A

those that need to be folded → the composition is vey important because the remodeling of these sugars is crucial for the folding of the protein

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24
Q

where is the sugar Asn-X-Ser/Thr synthesized?

A

membrane of the ER → starts in the cytosol, and then due to a flippase, the structure is inserted into the lumen of the ER

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25
Q

once the synthesis is complete and a sugar has been created, what enzyme binds?

A

oligosaccaril-transferase (OST) → is able to bind the sugar to the asparagine in the consensus sequence on the nascent protein

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26
Q

LEARN CALRETICULIN / CALNEXIN PATHWAY

A

p. 3-4

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27
Q

what is mannosidase?

A

a timer

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28
Q

how does mannosidase function as a timer?

A

once mannosidase I cuts these mannoses, UGGT is not able to re-glucosidate the protein anymore → once mannosidase I cuts, the protein can be degraded and it will be recognized by the degradation system

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29
Q

what proteins have n-glycans?

A

NOT ALL PROTEINS → only proteins with asparagine bound in the Asn-X-Ser/Thr sequence

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30
Q

what other step of processing occurs in the ER?

A

the formation of disulfide bonds (SS)

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31
Q

a disulfide bond is a characteristic of what type of protein?

A

a protein that has to be secreted

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32
Q

what type of proteins don’t usually have SS bonds?

A

cytosolic proteins

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33
Q

what does the formation of SS bonds give to the protein?

A

stability

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34
Q

describe the oxidation level of the ER compared to the cytosol:

A

the ER is more oxidizing than the cytosol

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35
Q

what 4 things do the formation of disulphide bonds help achieve?

A
  • stability of proteins
  • compactness
  • polymerization
  • QC
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36
Q

why do we need SS bonds for polymerization?

A

we can have interchain SS bonds that link two different polypeptides

37
Q

what is the function of oxidoreductases?

A

catalyze the formation, disruption, or isomerization of disulfide bonds in secretory proteins

38
Q

what is the most famous oxidoreductase protein?

A

PDI (protein disulfide isomerase)

39
Q

how are these oxidoredctasaes able to catalyze an oxidation of a secretory protein?

A

there is a enzyme which has a disulfide bond and a protein that needs to form one → the enzyme is able to transiently interact covalently with the protein so the enzyme will donate the SS bond to the protein the donation of the SS bond is oxidation

40
Q

what needs to happen if a protein is not able to fold and has to be degraded, but has already formed a SS bond?

A

the protein needs to be reduced and this protein is an oxidase → we have the formation of a covalent intermediate so the protein can be reduced and the enzyme can be oxidizes

41
Q

what is oxidation?

A

the enzyme at the beginning is oxidized and then reduced

42
Q

what happens in reduction?

A

in the reduction of the cargo protein the enzyme is reduced and at the end is oxidized

43
Q

what happens during isomerization?

A

the enzyme is reduced at the beginning and at the end (if the wrong SS is formed by mistake)

44
Q

can certain enzymes have more than one function?

A

yes - if you have an oxidoreductase, once it has oxidized a protein it will be reduced, and has to be re-oxidized to work again

45
Q

how can PDI be recharged once it is reduced?

A

Ero1 is oxidized and it donates its SS bond to PDI (at the end is reduced)

46
Q

how is Ero1 re-oxidized once it has given its SS bond to PDI?

A

it gives the reducing equivalent to molecular oxygen → we now have oxidized Ero1 and H2O2

47
Q

what effect does H2O2 have on a cell?

A

it is dangerous in a high amount

48
Q

what detoxifies H2O2 to water?

A

GPX7 and GPX8

49
Q

how else can H2O2 be detoxified and used?

A

it can be used by PRX4 to obtain an oxidized form, that is able to donate a SS bond to PDI

50
Q

what types of cells must be produced and secreted in every cell compartment?

A

native proteins

51
Q

what is one of the main QC systems in eukaryotic cells?

A

calreticulin / calnexin cycle

52
Q

what does the first step of the quality control ensure?

A

ensure that the proteins are correctly folded so they can proceed to the Golgi compartment

53
Q

what is the function of IgM?

A

a polymeric protein and is the first response that we produce against pathogens

54
Q

what is the first step of IgM formation?

A

the formation of the structure at the base of all immunoglobins: the monomers of IgM - two heavy chains and two light chains

55
Q

what is the heavy chain of IgM bound by?

A

BIP

56
Q

what is the second step of IgM formation?

A

polymerization → occurs through the formation SS bonds between the cysteine that are present at the C-terminals of the heavy chain

57
Q

what can only produce the SS bonds between cystines on IgMs but not polymerize them?

A

B cells

58
Q

what cells can polymerize the bonds on IgM cells?

A

plasma cells

59
Q

why is the heavy chain of IgM retained?

A

because it binds to BiP and BiP remains in the ER

60
Q

what else is retained in the ER besides the heavy chain of IgM?

A

the monomer → there is a cysteine at the C terminal that is not involved in a SS bond

61
Q

what is the first step of quality control in the secretory pathway in the ER?

A

proximal quality control → ensure the folding of monomeric proteins or of proteins that have to form dimer that are linked by noncovalent interactions

also controls the assembly of monomer of polymeric structures linked by SS bonds

62
Q

what does the second step of quality control in the secretory pathways control?

A

controls the assembly of monomers that compose polymeric structures linked by SS bonds

63
Q

what happens if a protein is not folded correctly and reaches the Golgi?

A

it will be brought back

64
Q

what can we consider the ER as?

A

chromatography column

65
Q

what two reasons are PDI, calreticulin, BiP, and Ero1 not normally secreted from cells?

A
  1. these enzymes are part of the matrix of the column, they interact with one another and form a matrix of folding enzymes in the ER
  2. a majority of these enzymes have a specific C-terminal sequence (KDEL)
66
Q

what is KDEL?

A

an aminoacidic sequence (lysine, aspartic acid, gluatamic acid or leucine) or small variance → receptor waits in the Golgi and will catch proteins with a KDEL (PDI, calreticuliun, BiP, or Ero1) and bring them back to the ER to ENSURE HOMEOSTASIS

67
Q

What is the ERGIC?

A

the compartment between the ER and the Golgi

68
Q

some structures like Ero1 do not have KDEL, so what do they bind to?

A

they bind to ERp44 which has its own KDEL at the C-terminal and brings them back

69
Q

what is special about Ero1?

A

it has a function both inside and outside the ER

70
Q

what is the main player of secondary quality control of oligomeric proteins linked by SS bonds?

A

ERp44

71
Q

what is special about ERp44?

A

it has only one cysteine, so it cannot act as a an oxidase or as a reductase

72
Q

what is Erp44 crucial for?

A

Secondary quality control: the QC of covalent link oligomers secretory proteins and is crucial for the intracellular localization of some ER enzymes which have a C-terminal KDEL-like sequence

72
Q

in the ER, what is the conformation of Erp44?

A

closed → the tail covers the active site so it is not able to bind to a substrate

72
Q

what does Erp44 bind to that helps it move from the ER to the Golgi compartment?

A

the cargo receptor ERGIC-53

72
Q

why is the Golgi more acidic than the ER?

A
  • the lysosome (most acidic organelle) exchanges material with the Golgi
  • in the Golgi there is GPHR which actively pumps protons inside the Golgi and helps to maintain the pH of the Golgi
73
Q

what is the environment of the Golgi high in?

A

zinc

74
Q

what do many transcription factors need zinc for?

A

to maintain their conformation

75
Q

zinc cannot stay free in the cell - it is imported by different transporters and in the cytosol it is bound by what?

A

metal carrier proteins like metallothionein

76
Q

in the secretory pathway, zinc is actively pumped into the Golgi by four different zinc transporters:

A

ZnTs 4,5,6,7 → important for importing zinc into the secretory compartment

77
Q

what happens when Erp44 arrives in the Golgi?

A

the pH of the Golgi is lower and zinc is present, so the protein opens its tail and zinc binds allowing it to now interact with its substrate

78
Q

ERp44 is able to recognize unassembled structure, and do what?

A

isomerize the SS bond in order to help correct polymerization

79
Q

what disease is linked to zinc?

A

Ehlers Danlos syndrome

80
Q

what did they see in mice when ERp44 was silenced?

A

fragmentation - the collagen deposit was not working

81
Q

how is there a strict relationship between zinc homeostasis and bone development?

A

zinc can affect collagen folding and because of alterations signaling cascades, it is necessary for bone development

82
Q

how do ERp44 and zinc have a bidirectional relationship?

A

ERp44 binds zinc and in the presence of high zinc concentration ERp44 can formed a dimer in which 5 zinc atoms are inserted, it can be like a zinc buffer for the secretory pathway. ERp44 needs zinc for its activity
as a quality control and modulating the levels of ERp44 we have some kind of response in cells, so that we have the up-regulation of some zinc transporters

83
Q

how does ERp44 effect IgM?

A

controls IgM assembly

84
Q

why must ERp44 be an isomerase, and not an oxidase or a reductase?

A

it only has one cysteine → cannot be an oxidase because it does not have the bisulfate bond

85
Q

how could ERp44 control pro collagen trimer assembly and control the activation of collagen processing enzymes with zinc?

A

in the absence of ERp44, we could have less active collagen processing enzyme / effecting procollagen trimmer assembly

Molecular Cell Biology (10 decks)

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