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MCB 2050 - Second Half - Mullen > Lecture 8 - endomembrane system part 3 > Flashcards

Lecture 8 - endomembrane system part 3 Flashcards

1
Q

do membranes form de novo?

A

no, all membranes form from pre-existing membranes

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2
Q

Where are most membrane proteins and lipids synthesized?

A

ER, with the exceptions of glycolipids synthesized in the golgi

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3
Q

How are nascent ER membrane proteins and lipids distributed and or orientated in lipid bilayer?

A

asymmetric manner

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4
Q

Where are integral membrane proteins?

A

different regions of protein located on either cytoplasmic or exoplasmic

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5
Q

Where are peripheral membrane proteins located?

A

located on either cytoplasmic or lumenal side of ER membrane

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6
Q

Where are membrane phospholipids located?

A

distributed unequally between cytoplasmic and exoplasmic leaflets of ER membrane bilayer

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7
Q

What type of asymmetry is established at the ER?

A

asymmetry and maintained throughout rest of endomembrane system

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8
Q

Are cytoplasmic and exoplasmic faces of cellular membranes conserved throughout the endomembrane system?

A

yes

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9
Q

What are the four final steps in co translational translocation pathway?

A
  1. signal sequence cleavage - removal of n-term signal sequence by signal peptidase
  2. initial stages of glycosylation - covalent addition of unique carbohydrate s.c. to specific AA of nascent protein (required for proper folding. protein-protein binding)
  3. protein folding and assembly - nascent protein folded into proper 3D conformation and oligomeric assembly by molecular chaperones (reticuloplasms)
  4. protein quality control - misfolded and/or improperly assembled proteins recognized and degraded
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10
Q

What does the ER serve as?

A

a quality control site for nascent proteins since represents first compartment in endomembrane system

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11
Q

What are most proteins synthesized in the ER?

A

glycoproteins - linked to one or more sugar chains

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12
Q

What do sugar groups do for the protein?

A

aid in proper folding and serve as a binding site for other macromolecules that interact with the protein?

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13
Q

What is the most common type of glycosylation?

A

N-linked glycosylation

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14
Q

What is N-linked glycosylation?

A

addition of specific short chains of sugar monomers (linked together in specific order to form oligosaccharide) to terminal amino group of asparagine (N)

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15
Q

What are the two stages of N-linked glycosylation?

A

core glycosylation
core modification

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15
Q

What is core glycosylation?

A

various ER membrane-bound glycosyltransferases synthesize core oligosaccharide

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15
Q

What does tunicamycin do?

A

blocks first step of N-linked glycosylation preventing proper folding of nascent ER proteins

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15
Q

What are the steps to core glycosylation?

A
  1. addition of first sugar to dolichol phosphate
  2. glycosyltransferases continue to add sugars at specific positions on growing core oligosaccharide
  3. transfer of core oligosaccharide from dolichol lipid carrier to nascent soluble membrane protein while being synthesized (empty dolichol phosphate recycled)
  4. core oligosaccharides transferred to lumenal acing portions of nascent ER proteins with specific AA sequence motif: -N-x-S/T-
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15
Q

What is dolichol phosphate?

A

membrane lipid serving as membrane anchor and carrier for new growing core oligosaccharide

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16
Q

What occurs during core modification?

A
  • attached 14-sugar core oligosaccharides sequentially trimmed and modified
    2. two of 3 terminal glucose units removed (trimmed) by ER lumenal glucosidases
    3. subsequent removal and re-addition of last glucose unit important for proper protein folding assembly
    reticuloplasms and PDI bind to nascent glycoprotein
    ER lumen glucosidase removes last glucose unit from core oligosaccharide during latter step
    nascent protein released from reticuloplasmins
    4. one mannose unit removed by ER lumen mannosidase
17
Q

What proteins mediate N-linked glycosylation?

A

reticuloplasmins
protein disulfide isomerase (PDI)

18
Q

What are reticuloplasmins?

A

ER molecular chaperones, including BiP, calreticulin and calnexin
bind transiently to nascent ER proteins while being synthesized via sec 61 cotranslational translocation pathway to prevent misfolding or aggregation

19
Q

What is protein disulfide isomerase?

A

catalyzes formation of intra/intermolecular disulfide bonds

20
Q

What do disulfide bonds between cysteine residues on nascent proteins do?

A

promote proper folding and assembly by stabilizing their 3D conformation

21
Q

What does adding the core oligosaccharide to the nascent protein do in N-linked glycosylation?

A

also contribute to proper protein folding assembly and stability and participate in protein quality control

22
Q

What does the nascent glycoprotein do once assembled through N-linked glycosylation?

A

functions as ER resident protein or

transported via vesicles from ER to golgi where n-linked glycosylation continues then resides in golgi or moves to other compartments in endomembrane system,

23
Q

What happens if the nascent glycoprotein is misfolded/misassembled?

A

recognized by UGGT monitoring enzyme, it addes back a single glucose unit to the oligosaccharide core and then the misfolded protein binds again to calnexin, calreticulin and BiP to mediate proper protein folding again
the process is repeated until the protein is properly folded and assembled

24
Q

What is UGGT monitoring enzyme?

A

glucosyltransferase - serves as protein conformation sensing protein. recognizes hydrophobic residues usually masked inside correctly folded protein

25
Q

What is the ERAD (ER associated degradation) pathway?

A

if the nascent misfolded glycoprotein cannot bypass the improper folding step of removing a glucose

26
Q

What does the ERAD pathway involve?

A

AAA ATPase p97

27
Q

What is AAA ATPase p97?

A

ER membrane protein utilizes ATP hydrolysis to pull misfolded proteins across ER membrane into cytosol (retrotranslocation)

28
Q

How is cystic fibrosis related to the ERAD pathway?

A

most patients possess mutant transporter protein (not properly glycosylation) - degraded by ERAD rather than properly targeted from ER to plasma membrane

29
Q

What happens once the redirected misfolded nascent glycoprotein is in the cytoplasm from N-linked glycosylation?

A

oligosaccharide chains removed and protein is poly-ubiquitinated

30
Q

what is poly-ubiquitination?

A

protein linked to chain of repeating poly ubiquitin units

31
Q

What is ubiquitin (UB)?

A

small protein involved in diverse cellular functions

32
Q

What is mono UB?

A

serves as signal for targeting membrane proteins into intraluminal vesicles of late endosomes multivesicular bodies

33
Q

What is poly UB?

A

serves as signal for ER protein degradation and for most other cellular proteins destined for normal turnover

34
Q

What is poly UB degraded by?

A

proteasome

35
Q

What is a proteasome?

A

barrel shaped multi-subunit protein degrading machine located in cytoplasm and nucleus

36
Q

What are the steps for the proteasome degradation of poly UB?

A

UB protein binds to cap of lid of the proteasome
poly UB chain removed
protein threaded into proteasome and degraded via proteolysis
free AA are reused for new protein synth

37
Q

How can the ERAD pathway be overloaded?

A

if misfolded proteins accumulate in the ER to high levels - can lead to several diseases and results in ER stress

38
Q

What does ER stress signal?

A

unfolded protein response pathways (UPR)

39
Q

What are the three protein sensors that mediated UPR pathways?

A

Ire1
PERK
ATF6

40
Q

What is a protein sensor?

A

ER integral membrane-spanning proteins

41
Q

What do PERK and ATF6 both have?

A

ER lumenal facing stress sensing domains which bind to molecular chaperones (BiP) in ER lumen

42
Q

What happens in the PERK and ATF6 pathways in stress and non-stress conditions?

A

non stress - PERK and ATF6 sensors inactive by binding to BiP

in ER stress conditions UPR pathways are activated

43
Q

What are the steps to the PERK-mediated UPR pathway?

A
  1. BiP released from PERK to aid in folding of accumulating ER proteins
  2. PERK dimerizes and becomes active
  3. cytoplasmic facing kinase domains of activated PERK dimer phosphorylate (inhibit) eIF2alpha (required for protein synthesis)
  4. decrease in cellular protein synthesis and molecular chaperones (BiP) is available to focus on pre-existing proteins in the ER
  5. ER stress alleviated, if not cell death
44
Q

What are the steps to the ATF6-mediated UPR pathway?

A
  1. in ER stress, BiP released from ATF6 (BiP needed for folding accumulating misfolded ER proteins)
  2. active ATF6 moves from ER to golgi via transport vesicles
  3. at golgi, the cytoplasmic facing TF domain of ATF6 is cleaved off by a golgi-associated protease
    ATF6 TF domain targets to nucleus via an exposed NLS
  4. in nucleus, ATF6 TF domain upregulates genes encoding key proteins involved in ER quality control (reticuloplasmins, ER export components which move proteins out of ER to golgi, and ERAD components)
  5. ER stress is alleviated or cell death

MCB 2050 - Second Half - Mullen (14 decks)

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