Cell signalling Flashcards
Stages of cell signalling
- Ligand-receptor interaction
- Signal transduction
- Cellular response
- Ligand-receptor interaction
- the ligand/signal molecule is complementary in shape to a specific binding site on the receptor and attaches itself there
- the binding of the ligand to the receptor induces a conformational change in membrane-bound receptor. this change in shape activates the receptor, triggering downstream signalling pathways
- The activated receptor then interacts with another molecule/ dimerise with another receptor molecule
Structure of GPLR
- is a single polypeptide with 7 hydrophobic transmembrane alpha-helices
- has an extracellular ligand binding site
- has an intracellular G protein binding site
How does GP-LR work????
- the GPLR is inactive when not bound to a ligand. The G protein is inactive when bound to GDP
- When ligand binds to the extracellular side of the GPLR, the receptor is activated, inducing it to change its conformation
- The cytoplasmic side of the receptor then binds to an inactive G protein, causing the G protein to exchange GDP for GTP
- The G protein is then activated and dissociates from the receptor. Activated G protein binds to an enzyme, activating it. Once activated, the enzyme triggers signal transduction, leading to cellular response.
- Once the signal molecule is absent, GTP is hydrolysed back into GDP by GTPase enzyme found in the G protein subunit. the G protein thus dissociates from the enzyme and returns to its inactive form. the signal is switched off
Structure of tyrosine kinase receptor (RTK)
- is a single polypeptide chain with a single transmembrane alpha-helix
- has an extracellular ligand binding site
- has an intracellular tail that functions as tyrosine kinase and also contains a number of tyrosine amino acid residues
How does RTK work????
- before a ligand binds, the receptor exists as individual RTK monomers
- the binding of ligands to the extracellular binding sites of RTKs causes 2 RTK proteins to come together in the membrane, forming a dimer
- Dimerisation activates the tyrosine kinase function found in the intracellular tails of RTK
- each tyrosine kinase adds phosphate groups from ATP molecule to the tyrosine residues on the tail of the other RTK protein by cross-phosphorylation
- the activated RTK will trigger the assembly of relay proteins on receptor tails
- each relay protein will undergo a structural change, activating them. each activated relay protein triggers a signal transduction pathway, leading to cellular response
- Signal transduction
- signal transduction converts the signal to a form that can bring about a specific cellular response. the signal transduction pathway often requires a sequence of changes in a series of different relay molecules in a multistep pathway.
- signal transduction occurs via protein phosphorylation in a phosphorylation cascade and the release of second messengers. such pathways also allow for signal amplification
SIgnal transduction: Phosphorylation cascade
- protein kinases are enzymes that transfer phosphate groups from ATP to proteins (phosphorylation)
- Protein phosphatases are enzymes that remove phosphate groups from proteins (dephosphorylation)
- Many of the relay molecules are protein kinases
- each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade
- relay molecules are usually activated when they are phosphorylated and deactivated when they are dephosphorylated
Signal transduction: Second messengers
- small, non-protein, water-soluble molecules or ions
- as second messengers are small and water-soluble, they can readily diffuse throughout the cell.
- in addition to their job as relay molecules, they serve to greatly amplify the strength of the signal
- e.g. cyclic AMP and calcium ion
- participate in pathways initiated by GPLR and RTK
Second messengers: Cyclic adenosine monophosphate (cAMP)
- an enzyme embedded in the csm, adenylyl cyclase, when activated by G protein, can convert many ATP to cAMP molecules
- the cytosolic conc cAMP is elevated twenty-fold in a matter of seconds, amplifying the signal in the cytoplasm
- it does not persist for long in the absence of the hormone, because another enzyme, called phosphodiesterase, converts the cAMP to AMP, resulting in signal termination
Signal transduction: signal amplification
- the relaying of signals is a multistep process that allows for greater fine-tuning of cellular responses and for amplification of the signal. a series of signal amplification is known as cascade amplification
- each catalytic step in a cascade produces a larger number of activated products than in the preceding step
- thus, small amount of signal will give a large response as each activated enzyme molecule can convert many substrate molecules into products per unit time before being inactivated
- each molecule of protein kinase phosphorylates many molecules of the next kinase in the pathway
- the amplification stems from the fact that these proteins persist in the active form long enough to process numerous molecules of substrates before they become inactive again
- cellular response
the signal transduction pathway leads to a specific cellular response, which is the regulation of one or more cellular activities. response may occur in the cytoplasm or nucleus
advantages and significance of a cell signalling system
- specificity in the ligand-receptor interaction allows ligand/ signal molecule to elicit responses in specific target cells
- the ability of a signal molecule to activate many different target cells simultaneously allow for regulation and control of response
- signal amplification allows for one signal molecule to trigger a large cellular response
- one signal molecule can activate many signal transduction pathways to trigger numerous cellular reactions simultaneously
- the binding of signal molecule/ligand to receptor at csm can result in activation of gene transcription in the nucleus
regulation of blood glucose level by glucagon and GPLR signalling
- When blood glucose level falls below the set point, glucagon is released by alpha cells of the islets of Langerhans of pancreas to bring about responses in liver cells (but NOT muscle cells)
Ligand-recptor interaction:
1. Binding of glucagon to extracellular site of GPLR activates the receptor and causes it to change conformation
2. the cytoplasmic side of the receptor then binds to an inactive G protein, causing it to exchange its bound GDP for GTP
3. the G protein is activated and dissociates from the receptor. activated G protein binds to and activates adenylyl cyclase, which catalyses the conversion of large numbers of ATP to cAMP
Signal transduction:
4. cAMP, a second messenger, binds to and activates a large number of protein kinase A (PKA)
5. each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade
6. at each phosphorylation step, each activated kinase is able to activate a large number of the next kinase
7. At each catalytic step in the cascade, the number of activated product is always greater than those in the preceding step, resulting in signal amplification
8. the final protein to be activated is glycogen phosphorylate
Cellular response:
9. during cellular response, a large number of glycogen phosphorylate is activated, which catalyses glycogenolysis
10. CR also includes increase synthesis or activity of enzymes involved in glucogenesis
11. decrease glycolysis and glycogenesis
eventually increasing bgc back to the set-point
Signal termination:
- glucagon is released from the receptor
- the GTPase activity intrinsic to a G protein hydrolyses its bound GTP to GDP
- Phosphodiesterase converts cAMP to AMP
regulation of blood glucose level by insulin and RTK signalling
- When blood glucose level increases above the set point, insulin is released by beta cells of the islets of Langerhans of pancreas to bring about responses in liver, muscle and other respiring cells that would lower bg level back to set point
Ligand-recptor interaction:
1. Binding of insulin to extracellular site of receptor tyrosine kinase causes 2 RTK proteins to form a dimer
2. dimerisation activates the tyrosine kinase function found in the intracellular tails of RTK
3. tyrosine kinase adds phosphate groups from ATP molecule to the tyrosine residues on the tails of RTK protein by cross-phosphorylation
Signal transduction:
4. activated RTK will trigger the assembly of relay proteins on the receptor tails, activating them
5. Activated relay proteins will further recruit and activate other downstream relay molecules and protein kinases
6. each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade
7. at each phosphorylation step, each activated kinase is able to activate a large number of the next kinase
8. At each catalytic step in the cascade, the number of activated product is always greater than those in the preceding step, resulting in signal amplification
Cellular response:
9. increase rate of processes that remove glucose from blood
-> increase transport of glucose transporters to the csm to increase glucose uptake into the cell
-> increase glycogenesis
-> increase glycolysis
-> increase fatty acid synthesis
- decrease glycogenolysis, decrease gluconeogenesis
eventually decreasing bgc back to the set-point
Signal termination:
- insulin is released from receptors, the tyrosine residues are dephosphorylated by phosphatases and the dimer dissociates back into individual RTK proteins
- protein phosphatases inactivate protein kinases by dephosphorylation
