Flashcards
Cell Signalling IV
Cards in this deck (24)
- 1Enzyme linked receptorsTyrosine Kinase Receptors (TKRs)
- 2TKRs1. EXC domain binds ligand.
2. Transmembrane domain
3. IC domain, has TK
4. +Pi Tyr residues from ATP - 3PK cassesTK
serine/threonine kinases e.g. PKA/B/C - 4Binding to PK1. Ligand binds to monomer
2. Induces conf. Δ in EC dom., dimerise
3. Induces conf. Δ in IC domain.
4. Auto-Pi,reveals substrate BS on opposite R
5. Transphosphorylation.
6. +Pi-Tyr provides docking site for signalling molecule. - 5GF R signalling+Pi -> Grb2 -> SOS -> Ras GTP
- 6Insulin R signalling1. Unusual as adaptors are +Pi by receptor themselves.
2. +Pi on IRS provide docking sites for a multitude of signalling cascades.
3. Compensatory mechanism as Insulin R doesn't have many Tyr in IC domain.
(extension cord). - 7RasMonomeric G protein (acts like alpha SU)
+ When bound to GTP
Intrinsic GTPase activity to -
Accessory proteins required to cycle between +/- - 8+/- of RasGEFs -> +
GAP -> -
(Cycle) - 9Ras signal cascadeRas Y-Pi -> Grb2 -> SOS -> Ras-GDP -> Ras-GTP -> MEK _MAPK -> +Pi-TF
Ras-GDP -> Ras-GTP (SOS)
Ras-GTP -> Ras-GDP (GAP) - 10Insulin ReceptorOnly TK to not dimerise
Heterotetrameter in PCM
Alpha SU bind to insulin
Induces conf. Δ in TK -> trans/auto+Pi - 11Insulin R cascadeInsulin -> Alpha -> trans/auto-> IRS-1 -> PIP2 -> PIP3 -> PDK1 -> PKB -> Glut-4 vesicle translocation
- 12Why do this?Regulates glucose uptake
Vesicle translocates to PCM, fuses, takes up glucose, passes it back into cell. - 13Enzyme -linked RRecruit EZ from cytoplasm
e.g.
Cytokine R recruit JAK to help initiate cell signalling - 14MOA (6)1. Cytokine R lacks intrinsic K activity.
2. Recruit soluble TK i.e. JAK.
3. Ligand binding causes R dimerisation + JAK+
4. JAK + each other and R
5. Adaptor proteins recruited to +Pi-Tyr on R
OR
6. STAT TF directly to JAK - 15Preferable drug designSmall molecules favoured
- 16The proteindomains capable of strong+specific interactions w/ drug
Has cavity e.g. well defined catalytic cleft - 17Good/Bad targets?Good: R/EZ
Bad: TF (apart from Nuclear R's). - 18Common targetCompetitive binding to ATP binding region to prevent gamma-phosphorylation
- 19Nuclear ReceptorsLigand + TF
- 20Domain Structure:Mod. conserved ligand-binding dom.
Highly conserved DNA binding dom.
Highly variable N-term w/ 1(>) + Domains - 21Categorisation 1 based on MOA and distribution in cell when L absent (5)Category 1:
Steroid/androgen R.
Found in cyto associated w heat shock protein
Forms a homodimer
Once in nucleus recruits co-+'s to mod. chromatin/DNA Pol' activity. - 22Category 2In nucleus
Sit on response cell event (DNA)
Form heterodimer, always complexed to RxR
Core repressor keeps chromatin compact, preventing gene transcription. - 23Category 2 diagramYoooohohoho
- 24Anti-hormone drugse.g. Tamoxifen
Struct similar to hormone, binds to LBD
Allows R dimerisation + binding to DNA/gene promoter
Side chains rpevent correct structural rearrangement of R
Co-activator BS is BLOCKED.
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- Created by J yadonknow · Mar 31, 2018
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