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BMB > Transmembrane Signalling > Flashcards

Transmembrane Signalling Flashcards

1
Q

needfor cell signalling

A
  • interact with environment
  • intercellular signalling for in a multicellular organism - facilitates coordination eg of growth control
  • central regulation of metabolic functions of different tissues
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2
Q

cAMP and dictyostelium

A

unicellular form - release cAMP upon starvation - chemoattractant, enables aggregation into multicellular form

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3
Q

endocrine

A

specific organ/ gland secretes specific hormone into circulation which acts on distant cells

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4
Q

short range signals

A

paracrine - eg NO, GFs, cytokines

autocrine - amplify incoming signal

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5
Q

gap junctions and signalling

A

signals transmitted directly through pores in membrane

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6
Q

discriminating between different external signals

A

specificity and expression of receptors

signalling pathways activated by a particular receptor

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7
Q

common features of signal transduction pathways

A
  • amplification
  • specificity
  • adaptation
  • integration
  • modularity
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8
Q

lipid soluble hormones

A

diffuse into the cell, bind specific cytoplasmic receptors, translocate to the nucleus, the receptor-hormone complex interacts directly with the target DNA

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9
Q

second messenger

A

molecules that relay signals from cell-surface receptors to target molecules inside the cell
eg cAMP, DAG, Ca2+
changes in second messenger levels correlate with physiological effects of the first messenger, need a removal method

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10
Q

general model for a signalling pathway

A
  • specific receptor for the stimulus
  • transduction mechanism to transfer info from outside to inside, often uses amplification
  • effector system, eg enzyme generating second messenger, helps amplification
  • response element - eg protein kinase, delivers info to final target (ampl)
  • mechanism of signal termination
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11
Q

switch proteins

A

active, inactive states

G proteins, phosphorylated proteins

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12
Q

structural feature of signalling proteins

A

many protein-protein interaction domains

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13
Q

scaffold/ adaptor proteins

A

have multiple specialised domains which act as docking sites for other proteins
so can form large protein complexes

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14
Q

Grb2

A

an adaptor protein with 2 SH3 and a SH2 domain

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15
Q

NO signalling

A

local signal as is unstable

  • production by vascular endothelium, diffuse to vascular smooth muscle, stimulates guanylyl cyclase activity which converts GTP to cGMP, triggering relaxation - vasodilation
  • NO synthase is a calcium dependent enzyme
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16
Q

molecular action of NO on guanylyl cyclase

A

NO binds to the haem of GC, restoring a planar structure and causing a protein conformational change via movement of an attached histidine

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17
Q

pharmacology + the NO system

A

block NOS activity with arginine analogues: eg L-NAME - treat anaphylactic shock via increasing blood pressure (prevent vasodilation)
- viagra - blocks cGMP PDE5 , causing increased NO levels and sustained vasodilation in erectile tissue

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18
Q

3 steroid hormones

A

cortisol - stress - adrenal gland

  • oestrogen, testosterone - sexual dev
  • thyroid hormone - metabolism
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19
Q

nuclear receptor superfamily

A

TFs with ligand binding, DNA binding and transcriptional activation domains

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20
Q

glucocorticoid receptor

A

binds Hsp90 wo ligand (so inactive)
glucocorticoid binding displaces Hsp90 - enables binding to regulatory DNA sequences - associate with HAT for expression of target genes

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21
Q

thyroid hormone

A

absence of hormone - TH receptor is associated with a corepressor. hormone binding results in activation of transcription

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22
Q

roles of water-soluble hormones

A

maintain homeostasis, respond to external stimuli eg fight or flight, follow cycic/ deelopmental programmes (eg sex hormones)

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23
Q

examples of water soluble hormones

A

adrenaline, NA

peptide hormones

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24
Q

neurotransmitter

A

carries signals between neurones or from neurones to target cells

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25
Q

eicosanoids

A

lipid signalling molecules - leukotrienes, prostaglandins, thromboxanes
derived from arachidonic acid - from phospholipids

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26
Q

producing eicosanoids

A

leukotrienes - lipoxygenase pathway
prostaglandins, thromboxanes - by cyclooxygenase pathway
hydrolysis of membrane lipids - by phospholipases

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27
Q

cyclooxygenase

A

enzyme of pathway to generate prostaglandins and thromboxanes
target of antiinflammatory drugs - aspirin, NSAIDs - reducing inflammation and pain

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28
Q

calcium and phospholipase A2

A

binding of calcium to PLA2 promotes its translocation from the cytoplasm to the membrane. cPLA2 then phosphorylated by MAPKs

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29
Q

6 types of receptors

A
  • GPCRs
  • RTKs
  • receptor guanylyl cyclase
  • gated ion channel
  • adhesion receptor (integrin)
  • nuclear receptor
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30
Q

adhesion receptors

A

cell adhesion initiates intracellular signalling pathways which regulate other aspects of cell behaviour. eg GFs - cytoskeletal rearrangements resulting in cell movement/ shape changes
integrins - receptors for cell attachement to ECM, also interact with cytoskeleton

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31
Q

integrins

A

integrins - receptors for cell attachement to ECM, also interact with cytoskeleton

1 a and 1 B domain, eith a cytoplasmic domian (int w cytoskeleton), TM domain, extracellular domain
inactive - extracellular domain is folded
contact extracellular ligand - extracellular domain straightens, cytoplasmic tails move apart altering their interactions with intracellular proteins eg actin cytoskeleton

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32
Q

binding of integrins to ECM ..

A

activation of FAK (focal adhesion kinase)
phosphorylation of FAK - binding of signalling molecules eg the Grb2-Sos complex
activation of Ras, PI3K, PLCy.

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33
Q

3 types of protein kinase

A

Ser/ Thr
Tyr
Thr/ Tyr (unusual)

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34
Q

effects of protein phosphorylation

A
  • alter local charge density (insert negative charge)
  • alter shape as well as local charge density
    ==> change in protein activity and capacity for interaction with other proteins
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35
Q

how does protein phosphorylation enable diversification of signalling pathways?

A

kinases are not specific to 1 substrate, pathway branches

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36
Q

protein kinase specificity

A

depends on primary sequence surrounding the target amino acid, some kinases have consensus sequences while some have broad specificity

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37
Q

RTK structure

A

extracellular ligand binding domain, single TM a helix, cytosolic domain with Tyr kinase activity

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38
Q

RTK activation mechanism

A

ligand binding - dimerisation - autophosphorylation

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39
Q

experiment on RTK activation mechanism

A

insulin receptor = already a dimer
produce chimeric receptor with insulin R extracellular domain and EFG TM/ cytosolic domain - could only transmit signals when occupied by insulin, so dimerisation was not sufficient for activation

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40
Q

effects of RTK autophosphorylation

A

receptor activated to phosphorylate other substrates
pY residues act as a template to bind SH2 domains of other proteins (receptor forms signalling complex - colocalisation of molecules allows interactions)

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41
Q

how can receptor phosphorylation act as a second messenger?

A

signalling proteins bind phosphorylated tyrosines via their SH2 domains
the catalytic activity of the clustered proteins act on substrates in the vicinity of the receptor kinase eg membrane lipids
eg PI3K, Ras

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42
Q

MAPK general activation

A

Downstream of RTK…

MAPKKK=ser/thr kinase, phosphorylates MAPKK, a Tyr/Thr kinase which phosphorylates and activates MAPK
downstream of MAPK are more kinases: MAPKAPs which regulate gene expression. eg JNK, p38 in the stress response
highly directed while highly diverse (branched) signal transduction

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43
Q

EGFR MAPK pathway

A

EGF - receptor dimerisation and autophosphorylation
Grb2 binds EGFR pY via its SH2 domain
Sos (Ras-GEF) binds Grb2 SH3 domain
Sos activates Ras (membrane-bound) by promoting exchange of GDP for GTP
Active Ras-GTP activates Raf (MAPKKK)
Raf activates Mek (MAPKK)
Mek activates Erk (MAPK)

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44
Q

Insulin receptor - general

A

uses same principle as other RTKs but only recruits insulin-receptor substrate 1 - which becomes phosphorylated and acts as a scaffold for other proteins

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45
Q

insulin receptor - structural changes

A

IR = a dimer of aB monomers, the a subunits bind insulin and the B subunits have the protein kinase activity
insulin binding activates this PK activity
each B phosph 3 Tyr on the other B
the autophosphorylation opens up the active site: movement of the activation loop makes room for the target protein in the substrate binding site

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46
Q

insulin receptor signalling pathway

A
  • IR binds insulin, autophosphorylates
  • IR phosphorylates IRS1
  • SH2 of Grb2 binds pY. Sos binds Grb2, then Ras, converted to active GTP-Ras form
  • Ras activates Raf
  • Raf activates Mek
  • Mek activates Erk
    Erk moves into the mucleus, phosphorylates nuclear TFs eg Elk1 is activated
  • phosph Elk1 joins SRF to stimulate transcription of genes needed for cell division
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47
Q

Indirect protein tyrosine kinases

A

cytosolic domains do not have catalytic activity, ligand binding causes dimerisation and cross-phosph of associated non-receptor protein tyrosine kinases

48
Q

example of a non-receptor tyrosine kinase

A

c-Src

of interest as the pathway is overactivated in many tumours

49
Q

regulation of c-Src - autoinhibition

A

an inhibitory Tyr of C terminus is phosphorylated under resting conditions, C terminus folds back and interacts with c-Src’s SH2 domain: obscuring the SH1 catalytic site

50
Q

3 groups of protein phosphatases

A
  • non-specific (acid, alkaline phosphatases)
  • phosphoserine/ threonine specific
  • phosphotyrosine specific
51
Q

protein tyrosine phosphatases

A

phosphatase domain has 11 residue signature sequence called CX5R motif - contains essential Cys, Arg residues
covalent Cys-phosphate intermediate - then hydrolysed

52
Q

protein ser/thr phosphatases

A

eg PP2A: regulation of metabolism

heterotriimer with scaffold, regulatory and catalytic subunits

53
Q

guanylyl cyclases

A

extracellular ligand binding domain, single TM a helix, cytosolic catalytic domain

54
Q

Notch

A

cleaved when receptor is activated by delta ligand, can directly modify transcription

55
Q

ethylene receptors - plants

A

empty receptor is active - without ethylene, the empty receptor activates a kinase which shuts off ethylene responsive genes. when ethylene is present, the receptor and kinase are inactive and the genes are transcribed
– relief of repression is a common mechanism in plants

56
Q

in which cell types are ion channels particularly important

A

nerve, muscle

57
Q

key properties of ion channels

A

rapid transport

can be highly selective

58
Q

nerve impulse and ion channels

A

AP travels along axon - membrane depolarises, Vm changes from -60mV to +30mV. due to rapid opening and closing of VG Na+, K+ channels

59
Q

ligand gated ion channels

A

open in response to binding of neurotransmitters/ other signalling molecules

60
Q

VG ion channels

A

open in response to changes in PM electric potential

61
Q

ligand gated ion channels

example

A

multisubuni - dif families have 3-5 subunits (can be homo or hetero)
nAChR - pentameric, each subunit has 4 TM a helices
P2X family - trimeric

62
Q

nAChR

A

ACh binding causes conf change which is transduced to the membrane domain
a helices lining the pore relax, removing the hydrophobic girdle blocking the channel and allowing ion flow

63
Q

structure of VG ion channels

A

Na+, Ca2+ - single polypeptide with 4 homologous domains, each containing 6 TM a helices
K+ - 4 separate polypeptide chains

64
Q

which helix of a VG ion channel is a voltage sensing helix

A

S4 - contains many + amino acids, so moves upon depolarisation - causing a conformational change which opens the channel

65
Q

ion selectivity in K+ channels

A

pore is lined with C=Os - displace hydration shell of K+ so K+ can pass through
Na+ is too small to interact and remains bound to water

66
Q

calcium signalling

A

intracellular Ca2+ is very low - use intracellular and extracellular Ca2+ as a second messenger - Ca2+ channels open upon dif stimuli
eg upon membrane depolarisation - leads to neurotransmitter exocytosis

67
Q

IP3

A

binds ER receptors, opens Ca2+ channels

IP3 = from PIP2 hydrolysis by PLC

68
Q

PLC

A

2 forms - 1 stimulated by GPCRs, 1 stimuated by tyr kinases

69
Q

PLC action

A

cleavage of PIP2 (a membrane phosphoinositol/ lipid) into IP3 (remains in membrane) and DAG (released to cytoplasm)

70
Q

experimental dissection of signalling pathways

A
  • protein-protein ints
  • probe roles of specific Tyrs with alanine screening
  • order proteins in pathway - genetic screen, mutant rescue
71
Q

elemental event - IP3/ IP3R

A

random channel opening - may trigger opening of adjacent IP3R and rise in Ca2+: spark/ waves

72
Q

IP3R

A

present on ER membrane

opening leads to Ca2+ release

73
Q

global opening of IP3Rs

A

need sufficient external stimulus, causes sustained rise in intracellular Ca2+

74
Q

IP3 signal termination

A

phosphatases remove phosphate from IP3, giving inositol
Ca2+ is exported from the cytoplasm - pumping into ER via SERCA, Na+Ca2+ exchangers and high affinity plasma membrane pumps

PLCB phosphorylated by PKA, PKC - lower enzyme activity

75
Q

downstream effects of calcium

A 
actions mediated via calmodulin (CaM) which binds Ca2+ via its EF hand domains, causing a conformational change which allows CaM to interact with target proteins
...
NO synthase
MLCK
adenylate cyclase
PMCA - plasma mem Ca2+ pumps
76
Q

downstream effects of PLC/ IP3 pathway

A

activate cellular activity/mitogenesis

77
Q

PI3 kinase

A

phosphorylates PIP2 to produce PIP3
PI3K is a dimer with a regulatory and catalytic subunit - modular structures which can interact with other molecules too.
activated by GPCRs, intracellular tyrosine kinases
effectors - Rac, a small GTP binding protein
alter cytoskeletal function - cell motility, vesicle trafficking, DNA synthesis

78
Q

GPCRs

A

highly conserved
alternate between 2 discrete conformations as ligand binding causes a conformational change to active state, allowing binding of heterotrimeric G protein to cytoplasmic face of receptor

79
Q

ligand binding to GPCR

A

ligand recognises binding pocket - which can be formed by external loops or deep within the cluster of transmembrane helices
initiates transmission of conformational change to intracellular domains of molecule - 5th and 6th helices are key to this signal transduction

80
Q

examples of GPCRs

A

receptors for peptide hormones, glycoprotein hormones, some neurotransmitters, amines, nucleotides, eicosanoids

81
Q

experiment which shows receptor mobility

A

(not definitive evidence!) - fusion of cell containing adenylate cyclase but not B-AR with cell containing B-AR but not adenylate cyclase - cell responsedto adrenaline by increasing cAMP. so B-AR or adenylate cyclase must be able to move in the membrane
though this is not good evidence as there could be movement of a cytoplasmic signal between the 2 proteins

82
Q

desensitisation/ adaptation of GPCRS - 2 mechanisms

A
  • PKA phosphorylates C-terminus of receptor - blocks capacity to bind to Gs but allows interaction with Gi - causing signal termination
    = heterologous desensitisation as any ligand that activates adenylate cyclase will have this effect. (dual effect as also turning ON an inhibitory pathway) (binary - all or nothing)

activity of a specific protein kinase - BARK - which phosphorylates a different site of the receptor which is only accessible in active receptors (dose-dependent), allowing recruitment of B-arrestin, an inhibitory molecule, blocking signal transduction through BAR - homologous desensitisation

83
Q

Gs

A

stimulatory, increases adenylate cyclase
a, B, y subunits
Ga has a ras-like G domain and a helical domain
GB has a helical domain and a B propeller
GB and Gy are tightly associated and act as a single unit

84
Q

How do GPCRs transduce signals?

A

ligand binding to extracellular domains transmits a conformational change to the cytosolic domain, allowing association with a specific G protein.

binding of the G protein promotes GDP for GTP exchange, leading to dissociation of the G protein from the receptor and dissociation of the a subunit from the By subunit

85
Q

G protein families

A

high level of conservation in GTP binding site

Gs, Gi and Gq like a subunits

86
Q

responses in which G proteins are involved

adrenergic receptor activation

A 
heart rate and contractility increase
BP increase
reduced blood flow to peripheral organs
bronchodilation
inhibition of insulin release
stimulate glycolysis and glycogenolysis
87
Q

a1
a2
B1/B2

A

a1: Gq, phospholipase C
a2: Gi, inhibit adenylate cyclase
B1/B2: Gs, activate adenylate cyclase

88
Q

adenylate cyclase

A

9 dif enzymes of similar structure,
2 TM domains separated by a cytoplasmic loop which is the regulatory and catalytic region.
convert ATP to cyclic AMP

89
Q

regulators of adenylate cyclase

A

Gsa, Gia, PKCa, CaM

90
Q

effects of cAMP

A

affects activity of PKA

91
Q

PKA

A

a tetramer of 2 regulatory and 2 catalytic subunits - the catalytic subunits dissociate upon binding of cAMP to each regulatory molecule

92
Q

Measuring adenylate cyclase activity

A

conversion of 32P radiolabelled ATP to cAMP - separate using ion exchange chromatography
radioimmuno/ binding protein assay - displace radiolabelled cAMP from antibody using test sample (whole cell extract)

fluorometric measurement - fluorescence of tagged PKA regulatory subunit changes upon binding cAMP (microinject)

93
Q

cAMP breakdown

A

by phosphodiesterases

can be regulated eg by protein phosphorylation, Ca2+/CaM

94
Q

cyclic AMP PDE

A

activated by cGMP

= cross talk: cAMP dependent processes can be modulated by ligands which activate cGMP production

95
Q

ACTH cAMP PDE example

A

ACTH stimulates aldosterone production by the adrenal cortex in a cAMP dependent manner. this causes an increase in blood volume. to limit this increase, atrial natriuretic factor is synthesised in the heart and leads to cGMP generation by activating receptor adenylate cyclase. cGMP binds and inactivates cAMP PDE, preventing PKA activation and turning off aldosterone production.

96
Q

thrombin - protease activated receptor

A

PAR1 is a receptor for thrombin, a serine protease. thrombin clips off a short peptide from the receptor, revealing a new N terminus which can bind and activate the receptor.
the receptor therefore contains a tethered ligand. synthetic peptides of the same sequence stimulate the receptor without cleavage. eg TRAP - thrombin receptor activatory protein

97
Q

Phospholipase C - activation by G proteins

A

leads to production of 2 second messengers - IP3 and DAG

98
Q

DAG

IP3

A

diacylglycerol - activates PKC

IP3- binds IP3R, leads to release of calcium from ER, CaM activates protein kinase C
protein phosphorylation - response

99
Q

photodetection in the eye - general

A

retinal cells deliver impulse to optic sensory neurones upon fall in internal calcium - which is regulated by cytoplasmic GMP

100
Q

rod and cone cells

A

rod cells - black and white vsion
cone cells - red, green or blue sensitive iodopsin
perceive light, send signals to the brain, rapid activvation and termination, adapt to changes in ambient light
cGMP = second messenger

101
Q

Rhodopsin

A

a G protein linked photoreceptor in the membrane of the rod outer-segment disc
retinal = chromophore - covalently linked within rhodopsin

light absorption converts cis retinal to the all-trans form - the conformational change activates the receptor

so retinal is the ligand for rhodopsin and the ligand only adopts an activatory conformation upon absorption of light.

102
Q

Rhodopsin pathway

A
  • light activates retinal, which activates Rhodopsin - the receptor
  • activated rhodopsin binds transducin, a heterotrimeric G protein - causing exchange of GDP for GTP, By subunit dissociation
    enables Gta to activate its effector, cGMP PDE (via Gta binding an inhibitor PDE subunit)
    PDE converts cGMP to GMP so cGMP levels fall
    falling cGMP levels causes closure of cGMP gated cation channels, causing hyperpolarisation
103
Q

what does falling cGMP levels cause in phototransduction

A

closure of cGMP gated cation channels

hyperpolarisation

104
Q

dark current

phototransduction

A

cell is partly depolarised due to influx of Ca2+ and Na+ eg via cGMP gates Na+ channels
cGMP PDE not activated

105
Q

why does phototransduction signalling start rapidly

A

activated rhodopsin can activate many Gts, Ca2+ channels bind 3 cGMP cooperatively

106
Q

termination of phototransduction signalling

A

trans retinal is rapidly hydrolysed and uncoupled from the receptor
rhodopsin kinase rapidly phosphorylates the receptor, which then associates with arrestin so cannot bind Gt (homologous desensitisation)
Gt has GTPase activity so inactivates

107
Q

adaptation in phototransduction

cGMP and Ca2+

A

guanylate cyclase is inhibited by Ca2+ so activity rises when Ca2+ internal falls, generating cGMP which can help return the channels to their open state (mediated by guanylate cyclase activating protein)
Ca2+ entry and cGMP formation establish an equilibrium - adaptation - allows eye to function over wide range of ambient light levels
steady state is disrupted by altered PDE activity/ rhodopsin desensitization

108
Q

GCAP

A

guanylate cyclase activating protein

binding Ca2+ inactivates

109
Q

colour vision

A

cone cells
dif forms of rhodopsin - different environment for retinal chromophore, different absorption spectra
eg vertebrates have 3 forms of rhodopsin which respond to red, green and blue light

110
Q

studying the G protein cycle - stable guanosine nucleotide analogues

A

non-hydrolysable analogues of GTP - a subunit becomes locked in a permanently active state

stable analogue of GDP prevents G protein activity

ALF4- structure matches that of PO42-, triggers release of By subunits as achieved by GTP

111
Q

inactivation of GTPases by covalent modification

A

cholera toxin acts on Gs and prevents GTP hydrolysis so the a subunit is constitutively active

112
Q

By sununits

A

also have signalling roles

113
Q

processes involving small GTPases (monomeric)

A

nuclear transport, cytoskeletal rearrangement, cell growth, differentiation, adhesion

114
Q

Ras

A

(RAt Sarcoma)
viral oncogene
activates TFs, controls gene expression
mutated forms are heavily implicated in cancer, with most mutations involved in the guanosine binding region

also undergoes a GTP/ GDP cycle however has low catalytic activity/not able to hydrolyse GTP to GDP quickly

115
Q

Ras structure

A

5 conserved regions
GTP binding region
switch regions - move upon GTP binding
effector domain interacts with downstream targets

116
Q

Ras pathway

A

isolated ras is catalytically inactive
GTP hydrolysis requires the action of GAPs

guanosine exchange is by GEFs
active in GTP bound form due to movement of switch regions

GAPs/ GEFs work by inserting residues into active site

117
Q

oncogenc ras mutations

A

low rate of GTP hydrolysis - constitutively active

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