Cell signalling: 8. Signals and receptors & 9. Transduction and response

Question 1

Why is cell commmunication important?

Answer 1

Organisms have many different cells - communication needed to function together - emergent properties

Question 2

What are the types of cell communication?

Answer 2

1. Local signalling (cells in direct contact with each other)
2. Long distance signalling (hormones / endocrine system used)

Question 3

Explain local signalling in cells

Answer 3

• direct contact between cells - via channel proteins (gap junctions)
• close proximity - communication via chemical signalling (synapsis)

Question 4

Explain long distance signalling

Answer 4

• Hormones and whole endocrine system used to communicate (ex for fight or flight response - adrenalin)
• Also in plants (Giberellins - for growth)

Question 5

What are the types of targetting in cell signalling?

Answer 5

• Autocrine
• Juxtacrine (via gap junction)
• Paracrine (chemical messengers, ex synapsis)
• Endocrine (signalling via bloodstream)

Andrew Jokes Praising Elizabeth

Question 6

What is the mechanism of accepting a signal in a cell?

Answer 6

1. Reception - receptor bonds to a signalling molecule (also called ligands)
2. Transduction - changing forms - message passed by series of protein changing shapes
3. Response - carried by an effector

One receptor might affect many relay molecules -> many responses to one signalling molecule

Question 7

What are the types of effector proteins and what are their responses?

Answer 7

Question 8

Which molecules are used as E for cell signalling?

Answer 8

• ATP
• GTP - from guanisine - more commonly used in signalling than ATP - E derived by hydrolysis into GDP + iP + E - by GTPase

Structurally similar

Question 9

Explain the replacement of GTP to GDP and GDP to GTP

Answer 9

GAP and GEF proteins aid in replacement

GTP is made not by adding a phosphate to GDP - completely new GTP is brought to the reaction

Question 10

Explain protein phosphorylation

Answer 10

• another way for cells to communicate - activation of certain proteins by adding a phosphate group (reversible modification - activation and be deactivated) - structural conformation changes once phsophorylated
• phosphorylation performed by protein kinases (activation)
• phosphates removed by protein phosphatase (deactivation)
• most commonly phosphates added to serine, threonine, tyrosine and histidine (am a)
• very common for proteins to have multiple activation sites for phosphorylation

Question 11

What are signalling cascades?

Answer 11

• chain signalling between different proteins - a signal is being amplified
• phosphorylation also used to amplify signals - signalling cascades (A protein phsophorylated - signals for 6 B proteins to phosphorylate - signals for 100 C proteins to phosphorylate and so on)

Question 12

What are the different types of receptors?

Answer 12

Question 13

Explain G-protein coupled receptors

Answer 13

• structure: form 2 parts = receptor + G protein (7 alpha helices)
• the receptor is integral transmembrane protein the - communicates outside to inside of the cell - G protein acts like a messenger between the receptor and target enzyme
• used as medication receptors
• roles: light sensitive in eyes, molecules in food as taste, scent molecules as smell, response to immune triggers, blood pressure, heart rate, digestion neurotransmitters - widely used - highly associated with disease
• when G protein bound to GTP - active state, when bound to GDP - inactive state

Question 14

Explain the transmission of a signal in G-protein coupled receptors

Answer 14

• signalling molecule binds to the receptor - receptor is activated
• G protein interacts - lost its GDP and gains GTP - receptor acts as a GEF because aids in exchange of GDP with GTP
• activated G protein travels along membrane to activate the enzyme (common activation - phosphorylation) - conformation of the enzyme is changed - active site exposed - catalysis of reaction performed - product obtained - activation used up - enzyme inactive
• G protein detaches - its GTP converted to GDP because E given to enzyme - ready to be activated by the receptor again
• example: mechanism for adrenalin (epinephrine)

Question 15

Explain tyrosin kinase receptors

Answer 15

• also called receptor tyrosin kinases (RTKs)
• transmembrane receptors - bind to extracellular ligand on the outside of the cell
• high numbers in eukaryotes - at leats 90 types in humans - 90 different functions
• enzyme active inside the cell - triggers internal signalling cascade - enzyme triggered kinase (phosphorylates other proteins by phosphate from ATP_)_
• ligand examples: HGF (human growth factor), NGF (nerve growth factor), EGF (epidermal growth factor), insulin
• receptor structure: two monomers - two parts: extracellular receptor binding site, intracellular downstream effect part

Question 16

Explain RTKs mechanism of action

Answer 16

• RTK inactive when the two monomers are apart - active when they are combined (friendship necklace)
• when ligands bind to both receptors - move together - form a dimer (membrane fluidity allows this move to happen)
• the enzyme part of RTK activated only when all tyrosines are phsophorylated - 6 ATPs needed -> fully activated
• relay proteins approach the activated enzyme - bind to active sites - relay enzymes activated - initiate cellular signalling (chain of protein kinase activation) - cellular response (effect)
• the activated enzyme of RTK can activate different relay proteins - from the activation of one RTK - many cellular signals - many cellular responses

Question 17

Explain phosphorylation cascade

Answer 17

Question 18

What is transduction?

Answer 18

Transduction - change of one signal into a different type of signal (ex phosphorylation cascade)

Question 19

Explain ligand-gated ion channels

Answer 19

• channel proteins but controlled by ions - open / closed
• used for influx of ions - cellular response
• ex synapsis - when neurotransmitter binds - ion channels open - influx of ions into postsynaptic neuron
• some channels can be opened by binding of ATP (P2X receptor family)

Question 20

Which receptors are intracellular?

Answer 20

Steroid hormone receptors

Question 21

Explain steroid hormone receptors

Answer 21

• some signalling molecules cross the membrane (no transport protein in the membrane) - usually lipid soluble (hydrophobic) - hormones (ex testosterone, oestrogen, cortisol) - bind to receptors inside the cell (usually very sensitive) - concentration control the size of the effect
• usually the final effect of these bindings - gene activation / inactivation - changes to mRNA - changes to proteins - hormone-receptor complexes regulate gene expression (by affecting transcription factors)

Question 22

What is cross-talk?

Answer 22

Cross-talk - when two different signalling molecules bind to two different receptors activating two different relay proteins -> one relay protein can activate / inhibit the other relay protein (Picture 3)

Question 23

Explain what are feedback loops and two examples

Answer 23

• Negative feedback - if exceeds conc - switches off / if conc lower - switched on
• Positive feedback - if exceeds conc - switched on - if conc lower - swicthed off
• Homeostasis - regulation of a process to keep a system stable in response to external stimuli
• Ex: lac operon (picture), p53 (the guardian of genome)

Question 24

Explain the feedback loop of lac operon

Answer 24

Question 25

Explain the feedback loop of p53

Answer 25

- p53 (the guardian of genome) - can stop the cell cycle, so DNA can be repaired or kills the cell via apoptosis (controlled type of cell death) - p53 short half life - constantly degraded - chaperone protein Mdm2 - carries p53 away from the nucleus and ensures that it is degraded by proteases - when things go wrong - reporter proteins communicate with Mdm2 not to degrade p53 - to ensure remain (done by reporter proteins) of p53 different ways: * disrupt binding of Mdm2 to p53; * remove marker from p53 which tells that it should be degraded; * change shape of p53 so Mdm2 cannot bind / make p53 able to bind to DNA to activate / repress genes (p53 acts as a transcription factor) - Human Papilloma virus (HPV) binds to p53 and inactivates it - nothing stops the cells form dividing when damaged - uncontrolled cell division - warts on skin form because of lack of apoptosis - more prone to mutations - cancer - overactivation of p53 also negative - unnecessary apoptosis, accelerated aging, injury to tissues

Question 26

Explain the ERK1/2 MAPK pathway

Answer 26

- RTK receptor - EGFR - mutations of the receptor cause cancer - relay protein Grb2 - activates Sos protein - GTP added to Ras protein (Sos is GEF for Ras) - activates Raf - activates Erk (also known as MAPK - more modern name) - transcription occurs - _Negative feedback loop_ - the more MAPK produced - the more production of Raf is supressed (many other activation / supression routes in the signalling cascade - important because decides if the cell will devide or undergo apoptosis) - Mutations of the EGFR receptor cause cancer - mutations of relay proteins cause cancer - Raf mutations cause cancer -\> drug targets (MAPK pathway is being researched for cancer treatment)

Question 27

How to stop a signalling cascade?

Answer 27

- Negative feedback - Remove the receptor via endocytosis - digest in lysosome / leave in vesicle for further use - Block the receptor with an arresting protein - can be removed to reactivate the receptor - Inactivate signalling proteins (ex negative feedback in MAPK pathway - MAPK supresses Raf)

Question 28

How are enzymes called which hydrolyse GTP into GDP and Pi

Answer 28

GTPases

Question 29

Removing GDP from GTPase nad replacing with GTP requires what

Answer 29

GEF

Question 30

Which proteins add a phosphate group and which remove

Answer 30

Add - kinases Remove - phosphatases

Question 31

For which receptor is nerve growth factor a ligand?

Answer 31

Tyrosine kinase receptor (RTK)