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Membranes > Signal Transduction > Flashcards

Signal Transduction Flashcards

1
Q

What different changes in cell behaviour can be done due to an extracellular signal?

A
  • altered metabolism
  • altered gene expression
  • altered cell shape or movement
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2
Q

What are 4 different types of signalling?

A
  1. contact dependent signalling
  2. paracrine
  3. synaptic
  4. endocrine
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3
Q

What is contact dependent signalling?

A
  • the extracellular signal cannot diffuse
  • attached to signalling cell
  • must be within close proximity
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4
Q

What is paracrine signalling?

A
  • signals are operating over short ranges
  • ligands have structural features that restrict their diffusibility
  • important for local modifications (e.g. in wound healing)
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5
Q

What is synaptic signalling?

A
  • nervous system
  • neuronal cell types
  • vesicle packets released at synapses
  • signalling can only occur within synapses
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6
Q

What is endocrine signalling?

A
  • specialised cell types that are releasing the signalling molecule into the blood stream
  • made available to target cells
  • long range signalling
  • e.g. beta cells releasing insulin
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7
Q

What are some specifications that a signalling machine must meet?

A
  • recognise the extracellular signal
  • generate an inter-cellular signal
  • elicits change in cell behaviour
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8
Q

What are some important properties of a signalling machine?

A
  • specificity
  • sensitivity (affinity for ligand)
  • dynamic range (range of concentrations and what responses are given)
  • duration (timing of the response)
  • processing (timing + shape of the signal. example is a sigmoidal graph, increasing conc will increase response. Or hyperbolic or all-or-none response)
  • integration (multiple signals impacting cells)
  • feedback and noise (positive and negative feedback, can amplify a forward reaction)
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9
Q

What is dynamic range?

A

difference between the smallest and largest usable signal through a transmission or processing chain or storage medium

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10
Q

What are the three classes of receptors that respond to signals?

A
  1. ion-channel coupled receptors
    - when ligand binds, conformational change occurs and ion is allowed in
    - e.g. GABA-A receptors, ligand is GABA, a inhibitory neurotransmitter
  2. g-protein coupled receptors
    - function by switching mechanism that involves GTP and GDP
  3. enzyme-coupled receptors
    - when ligand binds, leads to activation of a protein/enzyme catalysis process
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11
Q

What are G protein coupled receptors?

A
  • largest family of receptors
  • conserved structure
  • small molecule ligands (acetylcholine)
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12
Q

What is the structure of GPCR?

A
  • 7 transmembrane helices
  • extracellular ligand binding site
  • hydrophobic pocket is created by the helices which the ligand can bind
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13
Q

What happens when a ligand binds to the G-protein coupled receptor?

A
  • ligand binds in hydrophobic pocket
  • this elicits a transmembrane conformational change in the conformation of the helices
  • intracellular signalling is initiated by sensing the conformational switch
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14
Q

How does the GPCR signal via G protein switches?

A
  • 3 subunits, alpha, beta and gamma
  • GDP is bound to the alpha subunit (inactive state)
  • the ligand binding induces G protein binding to receptor
  • this induces the exchange of GDP to GTP
  • breaks up subunits ti Galpha and Gbetagamma
  • the GTP bound form can bind effectors (GTP binds to the alpha subunit)
  • GTP is hydrolyses back to GDP
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15
Q

What are GPCR’s inhibited by?

A

Arrestins

  • proteins which are recruited to the GPC when it is phosphorylated by GRKinase
  • arrestin locks the GPCR in its inactive state and degrades signal
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16
Q

Name an enzyme coupled receptor.

A

Receptor Tyrosine Kinases (RTKs)

17
Q

What are receptor tyrosine kinases?

A
  • an enzyme coupled receptor
  • have intrinsic kinase activity
  • phosphorylate substrates on tyrosine residues
  • ligand binding outside the cell activates the kinase inside the cell
18
Q

What is the structure of the tyrosine kinase domain?

A
  • have 2 domains linked together by a flexible region
  • N terminal domain contains an ATP binding site
  • C terminal domain contains substrate binding site and 2 alpha helices that determine specificity by the exposed amino acids in the helix
  • activation loop in the C terminal domain
  • contains one or more Tyr molecules
  • binds to catalytic cleft
19
Q

What 2 conformations is the activation loop in for tyrosine kinase domain?

A

unphosphorylated form - sits in the substrate binding site

phosphorylated form - the loop flips away from the binding site

20
Q

How do drugs inhibit RTKs?

A

bind to the ATP binding site on the N terminal domain

21
Q

How does the RTK become activated?

A
  • receptor dimerisation and inter-molecular phosphorylation
  • forced dimerisation activates RTK signalling in the absence of ligand
  • ligand acts to dimerise receptors
22
Q

What is achondoplasia?

A
  • commonly known as dwarfism
  • premature stopping of long bone elongation
  • mutations in FGFR3
  • causes transmembrane domain to dimerise in the absence of ligand
23
Q

What is crozoun syndrome?

A
  • genetic disease resulting in premature fusion of skull bones
  • mutations in the extracellular domain of FGFR2 which produces cysteine residues
  • leading to covalent dimerisation and activation of signalling in the absence of ligand
24
Q

What happens during ‘dominant negative’ receptor mutants?

A
  • a receptor is mutated to lack kinase domain
  • unable to signal even though they do bind the ligand as usual
  • can block a wild type receptor from signalling due to dimerisation
25
Q

What does activation of kinase lead to in RTK?

A
  • inter receptor phosphorylation of the tyrosine residues seen in C terminal tail of receptor
  • auto phosphorylation
  • recruitment of substrates
  • this causes binding sites for signalling proteins
  • activated signalling proteins relay signals downstream
26
Q

How does RTK recruits its substrates?

A
  • by specific recognition of pTYR by SH2 and PTB domains
  • these domains have tyrosine phosphate specific binding functions
  • binding site for phosphotyrosine and amino acid side chain
27
Q

How does the signal start from when the RTK is activated?

A
  1. The SH2 domain of the adaptor protein (Grb2) is recruited to the activated RTK tails
  2. Recognition domain SH3 in Grb2, recruits a protein called Sos (Ras-GEF)
  3. When Sos is recruited, it interacts with inactive Ras protein (which is a G-protein) and displaces GDP with GTP and activates Ras
  4. Can interact with downstream pathways
28
Q

What downstream pathway is activated by Ras GTPase?

A
  • MAP kinase cascade
  • sequence of kinases that phosphorylate each other
  • terminal phosphorylase (Erk) phosphorylates and initiates a range of changes of behaviour
29
Q

What is the MAP kinase pathway?

A
  1. Activated Ras protein binds to Raf
  2. Raf has one substrate which it phosphorylates- (Mek)
  3. Activated Mek has one substrate phosphorylates- (Erk)
  4. Erk phosphorylates many other proteins that undergo changes
30
Q

What is the PI3 Kinase pathway?

A

PI3 Kinase is an enzyme that phosphorylates a specific membrane lipid

  • increasing the conc of PI-3,4,5-triphosphate
  • that is a docking site for some proteins
  • so is recruiting proteins to the membrane hence changing its behaviour
31
Q

What does recruitment of effectors to the membrane due to PI-3,4,5-triphosphate do?

A
  1. recruits 2 protein kinases (PDK1 and Akt) with PH domains (domains that recognise PI-3,4,5-triphosphate)
  2. PDK1 phosphorylates Akt
  3. Akt activates mTOR (regulator of biosynthesis and energy balance)
  4. Akt also phosphorylates a protein called Bad
    - inhibits apoptosis in proteins
32
Q

What are cytokine receptors?

A
  • family of structurally related ligands and receptors
  • ligand recognition mechanism
  • act via receptor dimerisation
  • signal via activation of JAK (just another kinase lol) family through phosphorylation of the STAT family
33
Q

Why are cytokines medically important?

A 
erythropoetin:
- induces proliferation of erythroblasts
- treatment for anemia
G-CSF:
- induces the proliferation of neutrophils
- treatment with chemo
34
Q

What is the structure of the receptor that growth hormones (and cytokines) bind to?

A
  • has cytokine homology domain where 2 modules are at right angle to each other
35
Q

What is the structure of the growth hormone?

A
  • 4 alpha helices
36
Q

What is the activation mechanism for growth hormones to their receptors?

A
  • receptor dimerises through interactions between specific residues in the ligand with residues found in the loops of the 2 modules
  • binding of the ligand locks the dimerisation of the receptor
  • activates the downwards signalling
37
Q

What happens once the JAK kinase has been activated?

A
  • JAKs have 2 catalytic domains
  • the dimerisation results in phosphorylation of the C terminal region of the receptor
  • The C terminal region recruits STAT
  • STAT has an SH2 domain that binds to the phosphorylated receptor
  • STAT then becomes phosphorylated by the JAK Kinase
  • Then dissociates from the receptor and forms a dimer through the SH2 domains binding to the phosphorylated sites
  • STATs then relocate to the nucleus where is interacts with DNA

Membranes (19 decks)

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