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ANAT458 > integrins lect 29-30 > Flashcards

integrins lect 29-30 Flashcards

1
Q

what are intergins?

A

major metazoan receptor for cell adhesion

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2
Q

integrins are receptors for what organisms?

A

viruses and bacteria

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3
Q

what is the structure of integrins?

A

heterodimers; combination of 1 alpha and 1 beta subunit

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4
Q

how many types of integrins exist?

A

24 different combinasons

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5
Q

what subunit is synthesized in excess – pairs with many α-subunits?

A

B1

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6
Q

what are the 4 subfamilies of integrins?

A
  • laminin receptors
  • RDG receptors
  • collagen receptors
  • leukocyte-specific receptors
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7
Q

which integrin subunit has a di-sulfide bond?

A

alpha

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8
Q

beta subunit has a ________-rich domain

A

cysteines

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9
Q

many alpha subunit undergo what type of post-translational modification?

A

endoproteolytic processing at pairs of basic amino acids that is mediated by furin

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10
Q

what structure is found in all alpha subunits?

A

7 beta propeller motif

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11
Q

where is the MIDAS motif found in integrins?

A
  • alpha subunit: in the 7 B propeller motif, in the I/A domain
  • beta: toward N term
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12
Q

which integrin is the only one to not bind actin cytoskeleton? what does it bind?

A

a6B4: binds intermediate filaments

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13
Q

do all alpha subunits have a I/A motif in alpha subunit containing MIDAS?

A

no

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14
Q

what amino acids are almost always found in integrin-binding sequences?

A

D (aspartic acid) or E (glutamic acid)

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15
Q

what is the aVb3 integrin?

A
  • no I/A domain (therefore no MIDAS domain) in alpha subunit
  • involved in angiogenesis
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16
Q

describe an example of an integrin ligand that has a synergy site

A

fibronectin:
- FN9 = synergy site binding alpha subunit
- FN10 = RDG site binding beta subunit

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17
Q

what integrin does fibronectin bind to?

A

a5B1

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18
Q

how are fibronectin fibers formed?

A

fibronectin binds to integrin which are bound to the actin cytoskeleton.
fibronection dimerize and move following the actin/myosin interactions

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19
Q

name every player involved in fibronectin-actin linking

A

fibronection, integrin a5B1, actin binding proteins (vinculin, talin, paxillin, FAK), actin

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20
Q

what is cytochalasin?

A

drug that inhibit actin polimeryzation.
it also dissociates fibronectin because it is thightly linked to actin

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21
Q

what do disintegrins do?

A

proteins that block the function of integrins

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22
Q

what are 2 effects of disintegrins and via what integrins do they act?

A
  • block coagulation via aIIbB3
  • block angiogenesis via
    aVB3
23
Q

where are disintegrins found?

A

in snake venom

24
Q

what is in their sequence?

A

cysteine rich and RGD motif

25
Q

name 3 disintegrins

A

Eristostatin, Echistatin, Kistrin

26
Q

disrupting the different beta / alpha genes gave what results?

A

different phenotypes for each! shwoing their very different functions

27
Q

what disease is caused by a6B4 KO?

A

epidermis bullosa (lots of blistering)

28
Q

what disease is caused by aIIbB3 KO?

A

glanzmann thrombostheria (bleeding; like disintegrin effect)

29
Q

what disease is caused by B2 subunit KO?

A

inhibits leucocyte migration / adhesion to inflammation site

30
Q

more specifcially what type of epidermis bullosa is caused by a6B4 mutation?

A

hemidesmosal (disruption of hemidesmosome attachment of keratinocytes hemidesmosomes to BM laminin)

31
Q

what other mutations can cause epidermis bullosa? what type?

A
  • keratin mutation = simplex
  • plectin, a6B4 = hemodesmosal
  • laminin = junctional
  • collagen = dystrophic
32
Q

what are the 2 ways how integrins can get activated?

A
  • outside via ligand binding
  • inside via cytoplasmic tail separation
    (some are constituvely active)
33
Q

what movement of the subunit must happen for integrins to be activated?

A

separation of the alpha and beta subunit

34
Q

name one activator that helps separate integrin cytoplasmic tails?

A

talin

35
Q

what integrin is mostly in an inactive state (activation step is important for it)

A

aIIbB3

36
Q

how do integrins that do not have an alpha I/A domain get acti vated by a ligand? name an example

A

a4B6:
1- RDG domains of fibronectin binds beta I/A
2- C term of I/A moves down
3- integrin opens up
4- synergic site of fibronectin can bind alpha subunit

37
Q

how do integrins that have an alpha I/A domain like a2B1 get activated by a ligand?

A

1) collagen binds alpha I/A domain
2) C term helix moves down
3) makes beta I/A transmit conformational change to hybrid domain

38
Q

what links the cytoplasmic tails of the integrin subunits in an inactive state?

A

salt bring: ionic non-covalent interaction

39
Q

what is talin’s effect on integrins?

A

bind beta subunit to disrupt the salt bridge, leading to integrin activation

40
Q

how can talin get activated?

A
  1. cleavage relesing its integrin binding head
  2. PIP2 binding
41
Q

what regulates integrin activation?

A

talin and kindlin

42
Q

what does kindlin do?

A

connect integrin B subunit to actin via other adaptor proteins

43
Q

what is ILK?

A

integrin linked (pseudo)kinase: binds B subunit to actin via actin binding proteins and PINCH

44
Q

where do integrins cluster?

A

focal adhesion points!

45
Q

what is paxillin?

A

actin binding protein that binds ILK and actin

46
Q

why is integrin clustering important?

A

integrins alone have low affinity for their ligand

47
Q

remember: integrins bind actin via what end?

A

intracellular cytoplasmic tail

48
Q

integrins have low affinity but high what?

A

avidity (combined strength of multiple bond interactions)

49
Q

how does the integrin aIIbB3 get activated?

A

outside-in atcivation via binding to collagen outside blood vessels or thrombin

50
Q

once activated, what does aIIbB3 bind?

A

fibrinogen to aggregate platelets

51
Q

what are the steps of leucocyte extravasion?

A

1) weak interaction with selectins on endothelial cells
2) chemokine release -> GPCR -> integrin (ax a4B1) clustering
3) integrins can now interact with ICAMs
4) leucocytes enters tissue

52
Q

what integrin is involved in leucocyte extravasion?

A

a4B1

53
Q

check last slide integrins involvement in cancer / angiogenesis

A

ANAT458 (10 decks)

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