Question

oRelate these molecules to each other with regard to activation/inhibition, downstream consequences and functions.

oIllustrate the structures of a GPCR & RTK and relate to mechanisms of translation discussed previously.

oDevelop an experimental strategy to differentiate between these receptor groups and determine their structure with regard to the membrane.

oIllustrate/describe mechanisms of activation of GPCR and RTK.

oCompare and differentiate the role of G-proteins in the GPCR and RTK pathways.

oGiven a scenario, draw/interpret an epistatic pathway (including understanding how a mutation might affect the pathway)

oDescribe and interpret basics of signaling by TGF-b receptors & intracellular receptors, including type of ligand, and mechanism of signal transduction

Answer 1

1.

• Receptor tyrosine kinase is the plama membrane receptor that also have enzymatic activity.
• It catalysis the transfer of phosphate group from the ATP to the tyrosine group on the substrate.
• RTK inhibitors are present which makes RTK inactive .
• GPCR - G protein coupled receptors . This receptor exert its action by binding to GTP .
• When GDP is bound to GPCR they are inactive .

2.

• GPCR are transmenbrane molecules .
• They have seven transmembrane helices , the N terminal is present in the extracellular side and C terminal to the cytoplasm.
• When the receptor is activated by binding of the ligand , the signal transduction takes place downstream of the protein.
• The RTKs has extracellular domain, transmembrane domain and cytoplasmic domains. It also has two regulatory domains.
• Once the ligand binds to the extracellular domain , there occurs a conformational change in the catalytic site which is present in the cytoplasmic domain.
• This change causes transfer of phosphate group from ATP to the substrate molecule.

e)

• RTKs activate guanine nucleotide exchange factors (GEF) .
• These GEFs inturn activate number of GTP dependent proteins like RAS . They exchange GDP bound RAS to GTP -RAS and there by activate them.
• GPCR are G protein coupled receptor which is aativated by the by the presence of GTP. The energy present in the GTP drives the reaction.

f)

• In case of mutation , in GPCR or RTK , the proteins will be constantly in their 'on ' state.,
• They cannot be switched of which ;leads to continuous cell proliferation .
• This leads to tumour .
• Eg. RAS -GDP is inactivate state . RAS -GTP is active.
• When RTK is mutated , then GEFs are active and exchanges GDP in RAS to GTP which makes RAS active. The GEFs are unable to remove GTP from RAS and this leads to continuous activation of RAS and continuous cell proliferation occurs.