10 - Receptor Kinases - Williamson

Question 1

draw a diagram and explain how receptor kinases work

Answer 1

• low level of kinase activity by the kinase domain of the R monomers
• upon binding of the L, promotes dimerisation and the kinase domains are brought closer together
• cross P of the activation lip -> more active kinase
• allowing P of substrates
• substrates include enzymes/TFs that can then eg move into the nucleus to regulate gene expression

Question 2

what is the rate limiting step of these receptor kinases

Answer 2

movement of the activated substrate into the nucleus

Question 3

what are the downstream effects (generally) of the receptor kinase signalling? what type of receptor is this in contrast to ?

Answer 3

normally affects the transcription of DNA giving rise to medium/long term effects
- comparing to ion channels/GPCRs -> rapid responses

Question 4

draw a diagram highlighting how GPCRs lead to the activation of a G protein and state why RTK can signal much easier

Answer 4

• RTK can signal following R dimerisation. doesnt have to undergo a conformational change

Question 5

draw a diagram and explain how receptors for TGFB signal

Answer 5

• Type II Rs of the TGFB bind the TGFB ligand and dimerise
• T II receptor has a Ser/Thr kinase domain that is consitutively active
• L binds first to TGFB
• LR complex actively searches for a T I R and P its, active kinase on TI receptor
• SMAD2 that is floating in the cytoplasm binds to the activated kinase on TI and is activated
• P SMAD2 can open up (unP SMAD is autoinhibited)
• binding to SMAD4 means the open state is locked in place
• NLS exposed and the SMAD complex is targeted to the nucleus to activate transcription of genes

Question 6

what does TGFB control?

Answer 6

cell proliferation hence defects in this R play a role in cancer

Question 7

the protein:protein interactions involved in Smad signalling go on for how long?

Answer 7

lessthan 0.1s v rapidly

this is despite random walk of proteins promote interactions. v little direction of proteins until signalling

Question 8

how is the finding of RI by RII made easier? give an additional example of this

Answer 8

because finding in 2Drather than3D

- GPCRs activating G proteins

Question 9

even though T II is constitutively active, why is it that not effect normally occurs?

Answer 9

because the substrate is not bound

activity is due to co-localisation of the S

Question 10

how can signalling by smads be turned off?

Answer 10

1) activity of phosphatases remove P from smad and deactivate it. therefore size of signal depends on ratio between phosphorylation and dephospho rylation. effectively, more TGFB gives more P
2) one of the gene products of the activated Smad3/4 complex recruits a Smurf (smad ubiquitylation regulartoy factor) which targets smad for degradation