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Signal transduction > Part 3: Protein domains > Flashcards

Part 3: Protein domains Flashcards

1
Q

Domain: SH2

A

Src-homology2~100AA

2 alpha helices flanking beta sheet (antiparallel)

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2
Q

SH2 binding affinity

A

phosphorylated tyrosines

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3
Q

Domain: PTB

A

phsophotyrosine binding: ~100-150AA
beta barrel (antiparallel) followed by c-term alpha helix
binds in cleft between helix strands

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4
Q

PTB binding affinity

A

phophorylated tyrosines

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5
Q

Domain: SH3

A

src-homology 3: 60AA
Beta-barrel fold (2 antiparallel beta sheets)
binds in shallow hydrophobic pocket

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6
Q

SH3 binding affinity

A

prolines (-X-P-p-X-P)

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7
Q

PH domain

A

pleckstrin homolgy: ~120 AA
2 perpindicular beta sheets (antiparallel) followed by C term ampipathic alpha helix
binds in cleft between loops connecting strands

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8
Q

PH binding affinity

A

phosphorylated inositol phospholipids

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9
Q

molecular switches

A

kinase
phosphatase
Guanine nucleotide binding

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10
Q

protein kinases

A

protein phosphorylation

phosphate groups added to proteins using adenosine triphosphate

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11
Q

protein phosphotases

A

dephosphorylation

phosphate groups removed from proteins by hydrolysis

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12
Q

Guanine nucleotide binding

A

G protein cycle

  • Input signal Exchanges GDP for GTP
  • Exchange assisted by activated receptor for trimeric G, Guanine nucleotide exchange factors (GEFs) for monomeric G
  • Output signal–>hydrolysis (catalyzed by intrinsic GTPase for trimerG & w/ help from GTPase-activating proteins (GAPS) for monomeric G
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13
Q

Criteria of receptors

A

display specificity by detecting only those signal molecules the cell wants to perceive

  • appropriate binding affinity (Kd) for the signaling molecule in order to detect it at the likely concentration in the vicinity of the cell
  • transmit the message of the signaling molecule by modulation of further component in the signaling cascade
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14
Q

Receptor classes

A

intracellular

cell-surface

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15
Q

cell surface receptors

A

Ligand gated ion channel
G-protein coupled
Enzyme linked
cytokine

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16
Q

Ligand gated ion channel action

A

Binding of ligand changes ion permeability of plasma membrane and allows passage of specific ions

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17
Q

Ligand gated ion channel system

A

synaptic

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18
Q

Ligand gated ion channel ligands

A

neurotransmitters

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19
Q

Ligand gated ion channel binding

A

Kd=10^-6 to 10^-3 (very low affinity)

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20
Q

Ligand gated ion channel control

A

acute regulation (release of NT-containing vesicles from neurons; contraction of muscle cells) long lasting activation of Ca-sensitive gene expression

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21
Q

Ligand gated ion channel examples

A

cation-selective: excitatory (nicotinic ACh, glutamate)

anion selective: inhibitory (gly, GABA)

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22
Q

Ligand gated ion channel Drugs

A

psychotropics, anesthetics, anticonvulsants, drug abuse

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23
Q

Ligand gated ion channel: termination

A

Ligan removal occurs rapidly by:

  • diffusion away from receptor and synaptic gap
  • degradation by enzymes on cell surface (acetylcholinesterase)
  • reuptake into pre synaptic neuron

Formation of an inactive ligand bound state ensures brief periods of transduction

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24
Q

G-Protein coupled receptor action

A

binding of ligand activates heterotrimeric G protein which conveys signal to next component in pathway

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25
Q

G-Protein coupled receptor system

A

synaptic, endocrine, paracrine, autocrine

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26
Q

G-Protein coupled receptor ligands

A

NT, hormoes, cytokines (chemokines)

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27
Q

G-Protein coupled receptor binding

A

Kd= 10^-9 to 10^-6M

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28
Q

G-Protein coupled receptor control

A

mediation of sensory sytems (vision, taste, smell)

Acute regulation of critical physiological responses (cardiac contractility, metabolism, complex behavior)

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29
Q

G-Protein coupled receptor examples

A

Muscarinic ACh, beta adrenergic, rhodopsi

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30
Q

G-Protein coupled receptor drugs

A

antihistamines, anticholinergics, beta blockers, opiates

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31
Q

G-Protein coupled receptor structure

A

Transmembrane alpha helices
large ligands bind to extracellular loops, small bind in pocket
Extracellular subject to glycosylation
intracellular subject to phosphorylation

32
Q

heterotrimeric g proteins

A

coupling proteins
alpha subunit - ;argest (39-46kDa)
-hydrophilic; covalently attached to membrane
-many different forms
-guanine nucleotide-binding site and GTPase activity
-domains that interact with effector proteins

33
Q

beta-gama complex

A

dimeric complex of smaller subunits (35, 10kDa)

  • hydrophobic, covalently attached to membrane
  • similar form for different G-protein subtypes
  • some interaction with effector proteins
34
Q

G protein coupled receptor mechanism

A
  1. ligand binds
  2. Conformational change, recognition site exposure for G protein binding
  3. GDP/GTP exchange, G protein alpha dissociates from beta-gamma
  4. Subunit alpha binding to enzyme (release second messengers)
  5. Intrinsic GTPase activation, hydrolysis of GTP to GDP, release enzyme
  6. G-protein reformation with GDP, returns to receptor
35
Q

G protein coupled receptor termination

A

extracellular enzymes metabolize or inactivate many of the small ligands

  • Receptor mediated endocytosis accounts for some desensitization
  • receptor phosphorylation by protein kinases is the major mechanism of sensitization
  • protein kinase A–> receptor +/- ligand
  • GPCR specific protein kinases (GRKs)->receptor +ligand
36
Q

Caffeinated alcohol drinks: ethanol

A
  1. ethanol binds to allosteric binding site on GABA bound receptor
  2. Allows receptor to stay open longer
  3. causes membrane potential to become more negative
  4. Increases GABAs suppression of neural activity
  5. Increases dopamine release
37
Q

Caffeinated alcohol drinks: caffeine

A
  1. Caffeine blocks adenosine receptor on its G-protein (is an antagonist)
  2. cancels adenosines effect (suppresion of neural activity, increase blood flow)
  3. Allows increased neural activity
  4. Leads to blood vessel constriction, epinephrine release, increased alertness
  5. increases dopamine release
38
Q

Enzyme linked receptor action

A

Binding of ligand activates intrinsic enzymatic activity of cytoplasmic domain

39
Q

Enzyme linked receptor system

A

endocrine, paracrine

40
Q

Enzyme linked receptor ligands

A

hormones, growth factors

41
Q

Enzyme linked receptor binding

A

Kd= 10^-12 to 10^-9

42
Q

Enzyme linked receptor control

A

long-lasting changes in gene expression (cell division, programmed cell death, cell differentiation)

43
Q

Enzyme linked receptor examples

A

receptor tyrosine kinase (EGF,FGF,PDGF, insulin

receptor serin/threonine kinase: TGF-beta, BMP

44
Q

Enzyme linked receptor drugs

A

Cancer, type 2 diabetes

45
Q

Enzyme linked receptor structure

A

superfamily of more than 80 proteins
-each subunit is a single polypeptide chain consisting of: large extracellular n terminal for ligan binding, single transmembrane domain, intracellular C-terminal catalytic domain

46
Q

Functional Enzyme linked receptors

A 
mainly dimers (RTKS) and tetramers (serine/threonine kinases)
Variations: insulin receptor
47
Q

Receptor tyrosine kinase (RTK)

A
  1. inactive RTK
  2. Ligan binds->dimerization, kinase activation
  3. Active RTK-> autophosphorylation of tyrosine residues (cross phosph)
  4. Binding/activation of signaling proteins->initiation of cascade
48
Q

MAP kinase cascade

A

Mitogen-activated protein kinase cascade

  1. adaptor protein
  2. Ras activation protein
  3. active Ras
  4. activated MAPKKK (serine/threonine kinase)
  5. activate to MAPKK, threonine/tyrosine)
  6. activate to MAPK - effector protein (serine/threonine kinase)
  7. Phosphorphylates cystolic membrane proteins of nuclear gene regulatory protein
  8. Change in cystolic/membrane proteins or change in gene expression
49
Q

Enzyme linked receptor Serine/threonine kinase

A
  1. inactive
  2. ligand binding to type II, dimerization with type I, kinase activation and cross phosph of type I
  3. SMAD binding and phosphorylation , SMAD unfolding and activation
  4. SMAD dissociation, dimerization with different SMAD subtype, exposure of nuclear localization signal (NLS)
  5. Translocation to nucleus, altered gene expression.
50
Q

Enzyme linked receptor termination

A

Endocytosis down regulation

  1. Binding of ADAPTIN to exposed intracellular ligand receptor complex, binding of clatherin to adaptin, both cluster at invagination site
  2. clathrin polymerization, forms vacuole with coated pit
  3. Release of clatherin-coated vesicle into cytoplasm, shedding of clathrin coat, fucion of vesicle with endosome, dissociation of ligand-receptor complexes
  4. Potential recycling or transfer remains to lysosome for degredation
51
Q

Cytokine receptor action

A

binding of ligand facilitates association and activation of cytoplasmic enzymes, particularly tyrosine kinases, receptor lacks intrinsic enzymatic activity

52
Q

Cytokine receptor system

A

paracrine, autocrine

53
Q

Cytokine receptor ligands

A

cytokines, some GFs

54
Q

Cytokine receptor binding

A

Kd=10^-9 to 10^-6 M

55
Q

Cytokine receptor control

A

long lasting changes in gene expression (cell growth/differentiation)

56
Q

Cytokine receptor examples

A

Class I- interleukin: IL-2 dimers
Class II: interferon: IFN multimers
Tumor necrosis factor : trimers

57
Q

Cytokine receptor drugs

A

cancer, antivirals, immunosuppressives

58
Q

Cytokine receptor structure

A

great diversity, recruit broad range of intracellular signaling proteins
each subunit is a single polypeptide consisting of: extracellular N terminal ligand binding domain, single transmembrane, intracellular c terminal with different protein-protein motifs but no intrinsic enzymatic activity

59
Q

Functional Cytokine receptor

A

multimeric complexes (two or more)

60
Q

Cytokine receptor mechanism

A
  1. Inactive
  2. Cytokine binds–> dimerization of JAK
  3. JAK cross phosph, subunit phosphorylation
  4. STATs bind to subunit
  5. Phosphorylation of STATs, activated
  6. STATS dissociate and dimerize
  7. Translocation to nucleus–> altered gene expression
61
Q

Cytokine receptor termination

A

phosphatases remove tyrosine phosphates from receptor/STATS
SOCS (suppressor of cytokine signaling) protein inhibit STAT phsophorylation by binding/inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on receptor
-multimeric formation of receptor after ligan binding triggers endocytosis of ligand receptor complex

62
Q

Normal class II cytokine receptor mechanism (without ebola)

A
  1. IFN-gamma binds to JAK, activates it
    1b. Release of phosphorylated STAT1s and subsequent dimerization
  2. Binding of STAT1 dimer to importin alpha5 subunit of importin alpha5beta complex
  3. This is transported through nuclear por
  4. where it dissociates by Ran-GTP
  5. so STAT1 can bind to DNA targets (GAS)
  6. This leads to expression of antiviral respons.
63
Q

Ebola virus and Cytokine receptor pathway

A

EBOV VP24 protein competes with STAT dimer on the import complex
-Transport of infected complex thru nuclear pore
-which gets dissociated by Ran-GTP complex
causing a suppression of antiviral response

64
Q

Rate of formation Ligand receptor

A

k(on)[L][R]

65
Q

Rate of LR dissociation

A

k(off)[LR]

66
Q

equilibrium dissociation constant

A

k(on)[L][R]=k(off)[LR]
so
Kd=K(off)/k(on)
=[L][R]/[LR]

67
Q

small Kd

A

high affinity for ligand

68
Q

large Kd

A

low affinity for ligand

69
Q

Bmax

A

=total # of receptors=[R]o at t=0

[LR]=0

70
Q

At t(equilibrium)

A

Free receptor =[R]-[LR]
Free ;igand = [L]-[LR]=approx [L]o
bound ligand= [LR]

71
Q

Saturation binding relation

A

[LR]=[R][L]/(Kd+[L])
Bound= Bmax (free/(Kd+Free)

if free is&raquo_space; Kd, then bound=Bmax
if free =Kd, then bound =.5Bmax

nonlinear regression used to measure

72
Q

Saturation plot assumptions

A

equilibrium conditions
homogeneous, monovalent (1:1) populations of lgand and receptor
negligible ligand depletion (bound<10% of free)
Negligible inactivation of ligand and receptor
Negligible cell surface interactions

73
Q

Stachard plot

A

linearization of saturation binding equation
slope=-1/Kd
y int= Bmax/Kd
x int= Bmax

Advantage: visual evaluation is easy
Disadvantage: bound on both axes magnifies experimental error, saturation plot gives more accurate estimate of Kd, Bmax

74
Q

Dose response

A

Half Maximal Effective concentration = EC50

EC50

75
Q

Saliva stimulation in diabetes

A

Observation of reduced saliva in diabetic rats
Parotid gland: Kd=Kd for control vs diabetic but Bmax>Bmax
Submandibular: Kd control

Signal transduction (5 decks)

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