Heterotrimeric G proteins and the role of lipids in signaling. John Sondek, Ph.D. Depts. of Pharmacology and Biochemistry & Biophyscis
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1 Heterotrimeric G proteins and the role of lipids in signaling John Sondek, Ph.D. Depts. of Pharmacology and Biochemistry & Biophyscis
2 The GTPase cycle molecular switch
3 A GTPases is NOT a kinase
4
5 Two major regulators of GTPase cycle
6 Specific GEFs and GAPs for heterotrimeric G proteins
7 Active heterotrimer dissociates into a Gα subunit and a Gβγ dimer
8 G protein-coupled receptors as GEFs for heterotrimeric G proteins GPCRs are the largest family of cell-surface receptors for extracellular signals (superfamily of >1000 members) GPCRs respond to a wide range of inputs: hormones, neurotransmitters, odorants, tastants, photons of light, etc. ~60% of all clinical therapeutics act by affecting some aspect of GPCR signaling (e.g., agonist, antagonist, inhibition of natural ligand metabolism)
9 GPCRs are seven transmembrane (7TM) receptors
10 G proteins sense conformational changes of intracellular loops
11 G proteins sense conformational changes of intracellular loops
12 Active receptor stabilized nucleotide-depleted heterotrimer
13 GTP-loading catalyzes heterotrimer dissociation
14 Figure Molecular Biology of the Cell ( Garland Science 2008)
15 Rasmussen et al., Nature 450, 383 (2007)
16 R E G Bockaert & Pin (1999) EMBO J. 18:1732
17 Rhodopsin-like: - dopamine, adrenaline, serotonin (5HT) Ligandbinding pocket DRY -motif critical for G-protein activation IL8, fmlp PAF Thrombin: Special case of protease-activated GPCRs - Irreversible activation by N-terminal cleavage Palmitoylated cysteine Bockaert & Pin (1999) EMBO J. 18:1732
18 High-mol.wt. hormones: Glucagon Metabotropic glutamate/gaba/pheromone: Large Venus flytrap disulfide-linked ectodomain Bockaert & Pin (1999) EMBO J. 18:1732
19 2012 Nobel Prize in Chemistry G protein-coupled receptor drug membrane Brian Kobilka Brian Kobilka G protein (1994 Nobel Prize in Physiology or Medicine) GDP Robert Lefkowitz
20 The Gα subunit: Lipid modifications for membrane binding Exotoxin from Bordetella pertussis (whooping cough) catalyzes ADP-ribosylation of i-class Gα: Result? De-coupling from receptor Exotoxin from Vibrio cholerae (cholera diarrhea) catalyzes ADP-ribosylation of s-class Gα: Result? Constitutive activity since crippled as a GTPase
21
22
23 Gα contains a Ras-like domain and an all-helical domain Three switch regions have conformations that depend on which nucleotide is bound
24 Gα contains a Ras-like domain and an all-helical domain
25 This image cannot currently be displayed. Arginine finger is critical for GTP hydrolysis. This image cannot currently be displayed. transducin p120 GAP Ras-like domain Ras S3 R789 Helical domain R174 S1 S2 S1 S2 Gαt. GDP. AlF 4 Aluminum tetrafluoride ion mimics third phosphate of GTP and thereby activates GDP-bound Gα subunits. Ras/p120 GAP. GDP. AlF3
26 Arginine finger is critical for GTP hydrolysis Site of cholera activation; R>C mutation activates. Q>L mutation also activates by crippling GTPase function. R789 GDP AlF 4 Q200 Q61 S2 H 2 O R174 Mg 2+ H 2 O S2 GDP Mg 2+ AlF 3 S1 S1 Gαt. GDP. AlF 4 Ras/p120 GAP. GDP. AlF 3 For Ras-like GTPases, arginine finger is supplied in trans by GAPs. For heterotrimeric G proteins, the catalytic arginine is part of the alpha subunit.
27 Primary sequence characteristics of Gβγ dimers
28 Gβ forms a propeller; Gγ is an extended helical peptide. CAAX Sondek et al. Nature (1996) 379: 369
29 The switches of Gα are primary interaction sites with Gβγ (no interactions between Gα and Gγ!) Lambright et al. Nature (1996) 379: 311.
30 The switches of Gα are primary interaction sites with Gβγ (the N-terminal helix of Gα is also used) Lambright et al. Nature (1996) 379: 311.
31 Portions (purple) of all three subunits contact receptor Swap receptor specificity by switching C-termini? Inhibit coupling via C-terminal minigenes? Area of ADP-ribosylation via pertussis toxin (αi-class) Gilchrist et al. (2001) JBC 276:25672
32 Interface defined by structural features and biochemical evidence sugars membrane rhodopsin m retinal N-Myristoyl, S-palmitoyl S-Prenyl (GG or F) GDP Gα S3 S1 S2 Gβγ Regions of protein in purple are implicated in receptor interactions
33 Gα switches (I, II, III) are sensitive to bound nucleotide
34 Gα switch regions (I, II) directly interact with GTP
35 The four families of Gα subunits (-) Pertussis-toxin sensitive Gα subunits Adenylyl cyclase (+) (+) Phospholipase C-beta (+) Rho-GTP
36 Examples of G-protein effector systems G-protein subunit Effector Second messenger Gαs, Gαolf adenylyl cyclase [camp] Gαi1/i2/i3 adenylyl cyclase [camp] Gαq/11 phospholipase-cβ [IP 3 ] & [DAG] Gα12/13 RGS-box RhoGEFs [RhoA-GTP] Gατ (transducin) phospholipase-cε cyclic GMP phosphodiesterase [IP 3 ] & [DAG] [cgmp] Gβγ dimer or adenylyl cyclase or [camp] PLC-β & PLC-ε or ion channel flux [IP 3 ] & [DAG] K+ and Ca2+
37 Four Gβ subunits and one oddball
38 Blake et al. (2001) JBC 276:49267 Plenty o Gγ subunits
39 Gs = stimulatory G-protein linked to adenylyl cyclase activation (2nd-messenger generation) Adenylyl cyclase β2-adrenergic receptor on vasculature of skeletal muscles Adrenaline or Isoproterenol ( 1st messenger ) AC Second messenger + α s GTP γ β camp ATP Net result: Five-fold increase in [camp] i in seconds
40 Gαs GTPγS S3 S2 Complex of Gαs with cytoplasmic portions of Adenylyl cyclase S1 Gαs interacts with cyclase primarily through switches 1 and 2 forskolin Forskolin favors dimerization of cyclase domains IIC2 VC1 Tesmer (1997) Science 278:1907
41 Turning off the signal Multiple levels & multiple time-frames Reuptake/destruction of agonist (~millisec) Hydrolysis of GTP bound to Gα subunit (~sec) Reuptake/destruction of second messenger (~sec) Uncouple receptor from signal machinery (~sec/min) Remove receptor from cell-surface (~min/hr)
42 The R7 family Adapted from Hollinger & Hepler (2002).
43 RGS proteins stabilize the transition state for GTP hydrolysis
44 Figure 10-1 Molecular Biology of the Cell ( Garland Science 2008)
45 Figure 10-2 Molecular Biology of the Cell ( Garland Science 2008)
46 Figure 10-3 Molecular Biology of the Cell ( Garland Science 2008)
47 Figure 10-4 Molecular Biology of the Cell ( Garland Science 2008)
48 Figure 10-5 Molecular Biology of the Cell ( Garland Science 2008)
49 Figure 10-7b Molecular Biology of the Cell ( Garland Science 2008)
50 Figure Molecular Biology of the Cell ( Garland Science 2008)
51
52 Figure Molecular Biology of the Cell ( Garland Science 2008)
53 PLCs are phospholipases
54 PLC- β isozymes are classic effectors of heterotrimeric G proteins
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