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M2M Exam 3 wk 2 > import and export of nucleus > Flashcards

import and export of nucleus Flashcards

1
Q

The structure of the nuclear pore complex (NPC) consists primarily of a spoke complex:
It has an ______

A

octagonally symmetric cylindrical structure about 50nm tall around the axis of transport and a planar pseudo-symmetry through the nuclear envelope

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2
Q

Attached to the central framework are

A

8 cytoplasmic filaments and a nuclear basket formed from 8 filaments that join into a distal ring.

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3
Q

The linear dimensions of the NPC vary between species, but the ______ is conserved.

A

3D architecture

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4
Q

NPC External diameter is about

A

125nm

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5
Q

The ______ are a family of proteins which are the constituent building blocks of the NPC.

A

nucleoporins

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6
Q

_______ are repetitively arranged in distinct subcomplexes.

A

About 30 distinct nucleoporins (Nups)

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7
Q

There are a total of _____ per NPC.

A

500-1000 nucleoporins

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8
Q

A typical nucleoporin has a domain structure with an N terminus containing _______ and a C terminus rich in ______

A

multiple copies of the motif XFXFG (FG repeats)

heptad repeats characteristic for coiled-coil conformation.

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9
Q

a typical nucleoporin has two domains

A

N and C terminus

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10
Q

There are several models for the NPC permeability barrier to cargo, all of which involve _______:
(4)

A

FG Nups

  1. Selective Phase/Hydrogel Model
  2. Virtual Gate/Polymer Brush Model
  3. Forest Model
  4. Reduction of Dimensionality Model
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11
Q

Selective Phase/Hydrogel Model

A

Barrier is a 3-D sieve formed from inter- and intra-molecular interactions of FG-Nups

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12
Q

Virtual Gate/Polymer Brush Model

A

FG-Nups move vigorously back and forth to create a repulsive barrier with few stable
cohesive contacts

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13
Q

Forest Model

A
  1. FG-Nups adopt a mixture of extended (“tree”) and collapsed (“shrub”) conformations.
  2. The ends of several “trees” can form cohesive contacts to create a central tunnel
    (zone 1) that acts as a hydrogel, with a second route closer to the walls

(zone 2) acting as a virtual gate

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14
Q

Reduction of Dimensionality Model

A
  1. FG-Nups coat the inner surface of the pore to form a hydrophobic surface
  2. Hydrophilic unfolded chains extend into the central pore to create a selectivity filter
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15
Q

Recent work has shown that nucleoporins pull double duty as.

A

transcription factors regulating the activity of genes active during early development

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16
Q

Nucleoporins don’t regulate all genes, but are required for a subset of genes, including

A

developmentally regulated genes, which are turned on and off in a controlled manner during cell differentiation and tissue development.

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17
Q

NPC components:

A

The gene doesn’t go to the pore; the pore protein goes to the gene.

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18
Q

_______ may also be a potential marker for cancer.

A

Nucleoporins

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19
Q

Nucleoporins ______are highly overexpressed in some cancers, including _______.

A

Nup214 and Nup88

colon cancer and very aggressive forms of lung cancer

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20
Q

Karyopherins are the proteins that

A

the proteins that actually facilitate nuclear transport through the NPC. The act as mediators between the nuclear pore complex and the cargo being transported.

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21
Q

Karyopherins may act as

A

importins or exportins, and are part of the Importin-β super-family which all share a similar three-dimensional structure.

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22
Q

Karyopherins are ______ molecules composed ______

A

heteromeric

two major types of components, alpha karyopherins and beta karyopherins, that function together to transport molecules through the NPC.

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23
Q

Beta-karyopheryins

A

receptor family of karyopherins

directly interact with FG Nups
Some also interact directly with cargo

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24
Q

Alpha karyopheryins

A

adaptor family of karyopherins

facilitate cargo selective binding

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25
Q

Several other proteins such as _____ and _____ bind to karyopherins and participate in the transport process.

A

Ran GTP binding protein and cellular apoptosis susceptibility protein

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26
Q

Ran is a:

A

(RAs-related Nuclear protein)

small 25Kda protein that is involved in transport into and out of the cell nucleus.

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27
Q

Ran is a member of the ____ family

A

Ras superfamily.

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28
Q

Ran is a ______ protein that is essential for the ______

A

GTP binding

translocation of RNA and proteins through the NPC.

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29
Q

Ran exists in the cell in two nucleotide-bound forms:

A

GDP-bound and GTP-bound.

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30
Q

RanGDP is converted into RanGTP through the action of

A

regulator of chromosome condensation 1

(RCC1), the nucleotide exchange factor for Ran.

31
Q

Ran’s intrinsic GTPase-activity is activated through interaction with ______, facilitated by complex formation with _____

A

Ran GTPase activating protein (RanGAP),

Ran-binding protein (RanBP).

32
Q

GTPase-activation leads to the conversion of _____, thus closing the Ran cycle.

A

RanGTP to RanGDP

33
Q

Ran can diffuse freely within the cell, but because RCC1 and RanGAP are located in different places in the cell, the concentration of

A

RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes.

34
Q

RCC1 is located ______

A

inside the nucleus

35
Q

RanGAP is bound to _____

A

the nuclear envelope I

36
Q

This difference in location of the accessory proteins in the Ran cycle leads to

A

a high RanGTP to

RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus

37
Q

RanGTP =

A

nuclear export

38
Q

In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein
itself, with a higher concentration of_____

A

Ran in the nucleus than in the cytoplasm

39
Q

Cytoplasmic RanGDP is imported into the nucleus by _______

A

the small protein NTF2 (Nuclear Transport Factor 2),

40
Q

in the nucleus, RCC1 can then catalyze exchange of______

A

GTP for GDP on Ran

41
Q

Ran is involved in the transport of

A

proteins across the nuclear envelope by interacting with karyopherins and changing their ability to bind or release cargo molecules.

42
Q

Cargo proteins containing a NLS are bound by

A

importins and transported into the nucleus o Inside the nucleus, RanGTP binds to importin and releases the import cargo

43
Q

Cargo that needs to get out of the nucleus into the cytoplasm binds to

A

exportin in a

ternary complex with RanGTP

44
Q

Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex

A

dissociates and export cargo is released

45
Q

Nuclear localization signal and human disease:

A
  1. Male to female sex reversal

2. Cowden Syndrome

46
Q

Male to female sex reversal –

A
  1. XY female with external feminine genitalia but a lack of formation of both ovaries and testes
  2. Normally Importin Beta 1 binds to SRY to translocate to the nucleus, where it can
    upregulate transcription of target genes
  3. If SRY lacks an NLS, it will not be translocated to the nucleus and male sex determining
    genes will not be transcribed, resulting in male to female sex reversal
47
Q

Cowden Syndrome

A
  1. Autosomal dominant disease with high susceptibility to multiple hamartomas affecting
    derivatives of all three germ layers and by an increased risk of breast, thyroid, and
    endometrial neoplasia
  2. Protein of interest is PTEN, which is normally translocated by Kapβ o If no NLS, will not enter nucleus
48
Q

Nup Fusions in Cancer:

A
  1. NUP98/HOX fusions in acute myeloid leukemia (AML)

2. Aberrantly induces transcription of downstream HOX genes

49
Q

Role of NPC in Aging:

A
  1. No new NPCs are produced in post-mitotic cells
  2. This makes them prone to oxidative damage
  3. The result is a leaky nuclear pore
  4. This is seen in aging
50
Q

inhibiting nuclear translocation of calcineurin can prevent

A

myocardial hypertrophy.

51
Q

Nucleoporin: Human Nup 155

Tissue specific disorder:

A

Af, which is a cardiac disorder characterized by clinical arrhythmia

52
Q

Nucleoporin: Human Nup98

Tissue specific disorder:

A

Acute myeloid leukemia (and other hematological malignancies)
haematopoeitic stem cell proliferation

53
Q

Nucleoporin: Human Nup62

Tissue specific disorder:

A

primary bilary cirrhosis (autoimmune liver degen) for autoimmune antigen mutation

OR
Aitsomal recessive infantile bilalteral striatal necrosis (degeneration of the basal ganglia) for the homozygous missense Q391P mutation

54
Q

Nucleoporin: Human Nup358/RanBP2 (-)

Tissue specific disorder:

A

Familial cases of infection triggered acute necrotizing encephaly

55
Q

Nucleoporin: Human Nup 155
Mutation:

A

homozygous missense R391H

56
Q

Nucleoporin: Human Nup98

Mutation

A

multiple genomic translocations, which results in fusion of Nup98 fragment, including FG repeats to another gene

57
Q

Nucleoporin: Human Nup 62
Mutation:

A

autoimmune antigen or homozygous missense Q391P mutation

58
Q

Nucleoporin: Human Nup358/RanBP2 (-)

mutation:

A

heterozygous missense mutation T585M

59
Q

three layers of the NPC

A
  1. membrane
  2. scaffold
  3. barrier
60
Q

the layer that is functional s the

A

barrier layer. this acts as the selective gate

61
Q

the scaffold layer provides the

A

curvature of the NPC

62
Q

_____ in, ____ out

A

NLS

NES

63
Q

Ran.GTP:Importin/Exportin binding is _____, and blocks ______;

_____ relieves this block allowing ______

A

very tight

Ran’s intrinsic GTPase activity

RanBP1

RanGAP1 to activate Ran’s intrinsic GTPase by up to 105 fold

64
Q

_____ not cleaved during transport, so can be re-used

A

NLS/NES

65
Q

The translocation channel is a proteinaceous pore lined by

A

natively unfolded proteins that use hydrophobic interactions to form a selective filter.

66
Q

ImporVn α an _____

A

adapter protein:

> 7 family members in humans

67
Q

ImporVn β the

A

cargo carrier: >20 family members involved in both import and export, many members do not require an adapter protein

68
Q

Proteins (or protein complexes) may shuttle: contain both

A

NLS and NES

69
Q

Ran accounts for ___% of total cell protein

A

0.4% total cell protein ≈107 copies/cell

70
Q

The signals are typically exposed linear sequences of amino acids, often containing _____

A

multiple basic and/or hydrophobic residues.

They are not cleaved following transport.

71
Q

cargo transporters are generally members of the ____ family.

A

karyopherin

72
Q

Transport is regulated by the

A
  1. entropy barrier created by the Nups,
  2. the presence of the Ran.GDP/GTP gradient,
  3. the interaction of cargo transporters with nucleoporins, and
  4. cargo modifications/interactions that impact association with receptors.
73
Q

Diseases occur when proteins are

A

mislocalized, either because the selectivity barrier is compromised, or mutations perturb key interactions.

M2M Exam 3 wk 2 (11 decks)

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