Cell signalling: 8. Signals and receptors & 9. Transduction and response Flashcards
Why is cell commmunication important?
Organisms have many different cells - communication needed to function together - emergent properties
What are the types of cell communication?
- Local signalling (cells in direct contact with each other)
- Long distance signalling (hormones / endocrine system used)
Explain local signalling in cells
- direct contact between cells - via channel proteins (gap junctions)
- close proximity - communication via chemical signalling (synapsis)
Explain long distance signalling
- Hormones and whole endocrine system used to communicate (ex for fight or flight response - adrenalin)
- Also in plants (Giberellins - for growth)
What are the types of targetting in cell signalling?
- Autocrine
- Juxtacrine (via gap junction)
- Paracrine (chemical messengers, ex synapsis)
- Endocrine (signalling via bloodstream)
Andrew Jokes Praising Elizabeth
What is the mechanism of accepting a signal in a cell?
- Reception - receptor bonds to a signalling molecule (also called ligands)
- Transduction - changing forms - message passed by series of protein changing shapes
- Response - carried by an effector
One receptor might affect many relay molecules -> many responses to one signalling molecule
What are the types of effector proteins and what are their responses?
Which molecules are used as E for cell signalling?
- ATP
- GTP - from guanisine - more commonly used in signalling than ATP - E derived by hydrolysis into GDP + iP + E - by GTPase
Structurally similar
Explain the replacement of GTP to GDP and GDP to GTP
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
Explain protein phosphorylation
- 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
What are signalling cascades?
- 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)
What are the different types of receptors?
Explain G-protein coupled receptors
- 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
Explain the transmission of a signal in G-protein coupled receptors
- 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)
Explain tyrosin kinase receptors
- 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
Explain RTKs mechanism of action
- 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
Explain phosphorylation cascade
What is transduction?
Transduction - change of one signal into a different type of signal (ex phosphorylation cascade)
Explain ligand-gated ion channels
- 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)
Which receptors are intracellular?
Steroid hormone receptors
Explain steroid hormone receptors
- 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)
What is cross-talk?
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)
Explain what are feedback loops and two examples
- 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)
Explain the feedback loop of lac operon
Explain the feedback loop of p53
- 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
Explain the ERK1/2 MAPK pathway
- 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)
How to stop a signalling cascade?
- 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)
How are enzymes called which hydrolyse GTP into GDP and Pi
GTPases
Removing GDP from GTPase nad replacing with GTP requires what
GEF
Which proteins add a phosphate group and which remove
Add - kinases
Remove - phosphatases
For which receptor is nerve growth factor a ligand?
Tyrosine kinase receptor (RTK)
