3 - Signal transduction Flashcards
1
Q
Transduction
A
cascades of molecular interactions relay signals from receptors to target molecules in cell
• Multistep pathways can amplify a signal - a few molecules can produce a large cellular response
• Multistep pathways provide more opportunities for coordination and regulation of cellular responses
2
Q
Protein Phosphorylation
A
- In many pathways, the signal is transmitted by a cascade of protein phosphorylations
- Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation
- Phosphorylation most commonly occurs on serine, threonine (or tyrosine) residues
- Phosphorylation normally leads to protein activation
3
Q
Protein dephosphorylation
A
- Protein phosphatases remove phosphates from proteins - a process called dephosphorylation
- This phosphorylation and dephosphorylation system acts as a molecular switch - turning activities on and off or up or down, as required
- The activity of a particular pathway is therefore regulated by the ratio of kinase to phosphatase activity within a cell
4
Q
Small Molecules and Ions as Second Messengers
A
- The extracellular signal molecule (ligand) that binds to the receptor is a pathway’s “first messenger”
- Second messengers are small, nonprotein, water-soluble molecules or ions that readily spread throughout a cell by diffusion
- Second messengers participate in pathways initiated by GPCRs and RTKs
- Cyclic AMP and calcium ions are common second messengers
5
Q
Cyclic AMP
A
- Cyclic AMP (cAMP) is one of the most widely used second messengers
- Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal
- cAMP can be broken down by phosphodiesterase to form AMP, which is inactive
6
Q
cAMP as a second messenger
A
- Many signal molecules trigger formation of cAMP
- Other components of cAMP pathways are G proteins, G protein-coupled receptors, and protein kinases
- cAMP usually activates protein kinase A, which phosphorylates various other proteins
- Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase
7
Q
Cholera
A
- This disease is initiated by drinking water containing the bacterium Vibrio cholerae – over the past 200 years a series of pandemics have killed millions of people
- The bacteria colonise the small intestine (forming a biofilm) and produce an enzyme that acts as a toxin
- Affects a G-protein involved in regulating salt and water excretion
8
Q
cholera toxin
A
- Cholera toxin activates a G protein
- This modified G-protein is unable to hydrolyse GTP to GDP - hence is switched ON all the time
- This leads to constant activation of adenylate cyclase and continuous production of cAMP
- High cAMP levels activate the cystic fibrosis transmembrane conductance regulator (CFTR)
- Causes dramatic efflux of Clions and water from infected cells leading to watery diarrhoea
9
Q
Calcium Ions and Inositol Triphosphate (IP3)
A
- Calcium ions (Ca2+) act as a second messenger in many pathways
- Calcium is an important second messenger because cells can regulate its concentration
- Under normal conditions intracellular calciumconcentration is very low
- At a concentration that may be 10,000 times lower than in the blood stream (or plant cell wall)
- Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers
10
Q
Cytoplasmic calcium
A
actively pumped into the ER and/or mitochondria (or chloroplasts in plants) to keep cytoplasmic concentration of calcium ions low
11
Q
Calmodulin (CaM)
A
- This is a very specific calcium modulated protein - contains 4 Ca2+ binding sites
- Calcium binding induces conformational changes – CaM can bind to other proteins - causing activation or inactivation
- Proteins most often regulated by CaM are protein phosphatases and kinases but CaM also regulates the activity of adenylyl cyclases and phosphodiesterase (cAMP formation/breakdown)
- Plasma membrane Ca2+-ATPase (pumps Ca2+ out of cell) is also activated by CaM (reduces cytoplasmic Ca2+ concentration)
12
Q
Nuclear and Cytoplasmic Responses
A
- Ultimately, a signal transduction pathway leads to the regulation of 1 or more cellular activities
- Response may occur in cytoplasm or the nucleus
- Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus
- The final activated molecule in the signaling pathway may function as a transcription factor
13
Q
Fine-Tuning the Response
A
There are 4 aspects of fine-tuning to consider:
• Amplifying the signal (and thus the response)
• Specificity of the response
• Overall efficiency of response, enhanced by scaffolding proteins
• Termination of the signal
14
Q
Scaffolding Proteins and Signaling Complexes
A
- Scaffolding proteins - large relay proteins to which other relay proteins are attached
- Scaffolding proteins can increase signal transduction efficiency by grouping together different proteins involved in the same pathway
15
Q
Termination of the Signal
A
- Inactivation mechanisms are an essential aspect of cell signalling
- If the ligand concentration falls then fewer receptors will be bound
- The unbound receptors revert to an inactive state
- But also remember the example of how Ca2+ and CaM contribute to a negative feedback loop to reduce cytoplasmic Ca2+ levels
