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N
N N
N
CH3H3C
O
O
CH3
caffeine
Signaling via Ligand-Receptor Binding
Agonist - ligand binding to a receptor and eliciting a response
Antagonist - ligand binding to a receptor but not eliciting a response
R + L ↔ R∙L
Kd = [R][L]/[R∙L]
Bacterial Quorum Sensing
Increased cell density dependant signaling
Activation of Bio-film formation which affects bacterial resistance
Extracellular Signals
G Protein Coupled Receptors
Guanyl nucleotide binding protein:Minus ligand, α, β, and γ subunits associated with GDP (inactive bound form) and
Plus ligand, α subunit exchanges for GTP (active released form)
Signal propagation: Activate adenylate cyclase converts ATP to cyclic ATP
Signal resetting:GTP hydrolyzed to GDP and β, and γ subunits re-associate
G-Protein Cycle and Generation of Cyclic AMP
How is adenylate cyclase activated?
External Signal for G-Protein Activation
β2-adreneric receptor
Heterotrimeric G Protein
α, β, and γ subunits (blue, green, and yellow, respectively) associated with GDP (orange)
G-Protein Pathway Activation by Epinephrine
What is effective signaling? Specificity? Sensitivity?
Adenylate Cyclase Activation/Deactivation
Cyclic AMP Deactivation
Protein Kinase A Activation by cAMP
Protein Kinase A Regulation by Phosphorylation
Dephosphorylation blocks substrate from active site
Catalytic subunit: light green
Activation loop: dark green
Substrate target protein: blue
External Signal for G-Protein Activation
α-adreneric receptor is also activated by epinephrine and norepinephrine
IP3, a product of phosphatidylinositol bisphosphate hydrolysis signals a calcium influx and protein kinase C activation
Phosphoinositide Cascade
Calcium Binding Protein: Calmodulin
EF-hand protein familyExtended unbound form
Bent bound to a target protein
Ca+2 ions
Receptor Tyrosine Kinases
Operative for certain hormones and signaling molecules that regulate growth (e.g. insulin)
Ligand binding allows the receptor monomer to form a dimer unit with cytoplasmic kinase domain catalytically active
Insulin receptor
Insulin binding site
Insulin binding site
Extracellular region
Cell surface
α,β subunits: one in space-filling (red) and other in backbone-trace form (yellow)
Insulin Receptor Tyrosine Kinase Activation
Inactive form (blue)
Activation loop (dark blue)
Active form (green)
Activation loop (dark green)
Note:Activation loop swings out with Tyr phosphorylation
Ras- rat sarcoma virus
Ras Signal Transduction Pathway
Color coding: red inactive; green active
Ras Signal Transduction Pathway
Ras Signal Transduction Pathway
Protein phosphorylation can lead to subsequent gene activation
Lipid Hormone Signaling
Includes thyroid hormones that stimulate metabolism (right) as well as hormones for salt, water and reproductive functions
Do not bind to cell-surface receptors
Directly cross membranes to interact with intracellular receptors
Lipid Hormones: Eicosanoids
Regulation of blood pressure, blood coagulation, inflammation, pain and fever
Aspirin inhibits cyclooxygenase activity and therefore serve as a blood thinner