Address 7 Chapter 15 Cell flagging: Communication Bet

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Address #7 Chapter 15 Cell flagging: Communication Between Cells and Their Environment Overview of intracellular flagging: Initiation and reactions Axiom #7 Study hard and remain concentrated on your instructive objectives. Be that as it may, dependably have a reinforcement arrange! Keep in mind: while chance supports the readied mind, you can't generally be the place the lighting strikes.

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What are G-proteins? G proteins tie GTP: guanosine triphosphate. Control and open up intracellular flagging pathways Exist in two states 1) bound GTP: dynamic 2) bound GDP: latent (hormone, GF, tranquilize) Examples of GTPase proteins Ras, Cdc-42 Fig. 15.1

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Jennifer concentrates on G-proteins! The J Lo witticism: A point by point comprehension of the principal forms that oversee this GTPase cycle will give a premise to recognizing how cells transfer signals. G-PROTEINS

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GTPases and illness. Harm to these little GTPase switches can have calamitous outcomes for the cell and the creature. A few little GTPases of the Rac/Rho subfamily are immediate focuses for clostridial cytotoxins. Promote, Ras proteins are changed to a constitutively-dynamic (GTP-bound) frame in around 20% of human growths.

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G-proteins are firmly directed 3 sorts of embellishment proteins that regulate cycling of G-proteins between GTP/GDP 1. Crevices : GTPase-enacting proteins. Invigorate GTP hydrolysis. Inactivate G-protein. Case of a GAP: PLC b. 2. GEFs : Guanine nucleotide-trade variables: G-protein-coupled receptors (GPCR). Fortify separation of GDP (idle) from G-protein so GTP can tie (dynamic). 3. GDIs : Guanine nucleotide-separation inhibitors. Repress discharge of bound GDP (keep up G-protein in idle state).

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The heterotrimeric G proteins transmit signals from an assortment of cell surface receptors to catalysts and channels Stimulated by receptors Act on effectors Regulated by nucleotide exchange and hydrolysis

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Fig 15.3 The G Protein Cycle

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Minireview Translocation and Reversible Localization of Signaling Proteins: A Dynamic Future for Signal Transduction Mary N. Teruel * 1 and Tobias Meyer * 1 Department of Molecular Pharmacology, Stanford University Medical School, 269 Campus Drive, Stanford, California 94305 GTP is little and can diffuse quickly all through the phone Diffusion-Mediated Random Walk of Signaling Proteins Schematic representation of a 4 s in length arbitrary stroll of (left) a cytosolic protein, (center) a layer bound protein, and (right) a receptor. Recreated with MATLAB.

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GTP ties to GTPases. Hang on! Engines on vesicle with G-proteins. Intriguing thought: Some engines has GAP spaces (Myosin-IX) G-proteins may go about as engine connection variables. (Rabs)

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Rabs are individuals from the little G-protein family Rab 6: a GTPase for Kinesin Rab 27a: A GTPase for myosin-Va Defects in Rab27a cause Griscelli disorder

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Other G Proteins Rho Family of GTPases (joined pathways) Cdc 42 : actin-subordinate layer unsettling Rac: actin-subordinate film unsettling Rho : actin-subordinate central contacts (FAK), stress filaments Ras : expansion

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Ras Activation and the MAP Kinase Cascade Tyrosine Kinases, G-Protein coupled receptors See Fig. 15.2 Raf-1 (Map kinase) MEK (MAP kinase) ERK (MAP kinase) Nuclear administrative proteins Cytoplasmic substrates

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What does Ras collaborate with? Raf

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G proteins G protein structure G protein control

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Why do we think about the structure of the structure of G proteins: including the G an and G bg interface? The a subunit ties and hydrolyzes GTP-a : separates from G bg (firmly related) Both subunits ( an and bg , then actuate their individual effectors). Taking after hydrolysis of GTP to GDP, subunits reassemble and get to be dormant Ergo: contact surface between G an and G bg has major administrative significance. Fig. 15.11

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The direction of G proteins. Fig. 15.12

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A Ribbon Diagram of the G a,b,g The heterotrimer comprises of an a subunit that ties and hydrolyzes GTP and a couple of proteins, b and g , that are firmly connected with each other. The G a subunit is shown in light blue, the G b in green, and the g in dull blue

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A Schematic of the G b Propeller Structure The schematic demonstrates the relative position of the four successive strands in each of the seven sharp edges. Likewise demonstrated are the key WD rehash amino acids (see Figure 4). The seven symmetrically set surface Asps in the tight a few deposit turn between strands b and c are demonstrated by green cirles on the top surface of G . These are not the D of WD. The exceedingly preserved aromatics at the lower finishes of strands an and c are appeared by blue circles. The Asp of the characterizing WD, conceivably uncovered on the propeller's more extensive base surface, is demonstrated by a red circle. Every propeller has 4 b - sheets

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Take Home Message #1. Cells keep up their flagging yields by setting up a harmony between the nucleotide swapping scale and the hydrolysis rate What is the favored bound nucleotide in the resting cell? G-GTP or G-GDP?

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Answer: G-GDP In the basal state, G alpha discharges GDP at a moderate rate (0.002 s - 1 ) contrasted with its rate of GTP hydrolysis (0.05 s - 1 for G). This active adjust guarantees a low populace of actuated G protein particles, and keeps up the cell in a resting state. After official to agonist, G protein coupled receptors quicken G alpha subunit GDP/GTP exchange.  Receptors act as impetuses, accomplishing rate upgrades of up to 10 4 - overlay. As receptor-driven nucleotide trade turns out to be quick with respect to hydrolysis, the adjust of rates in the GTPase cycle changes. The new adjust expands the number of inhabitants in GTP-bound species, hence moving the cell to an actuated state. 

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Why do we require GAPs? To purchase kakis

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Answer The motor boundary to GTP hydrolysis is generous, permitting G proteins to keep up the dynamic flagging state for quite a long time, possibly hours. Thus, GTPase-actuating proteins, or GAPs, are required to help G proteins in hydrolyzing GTP.

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Take home message #2 Hydrolysis is the kill flag that prompts heterotrimeric G protein a  subunits (G a ) to separate their effectors. Note change in structure of GTP versus GDP bound G protein

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Why do we require GEFs?

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Answer The somnolescent state accomplished after hydrolysis ought to be comparatively extended without intercession; once more, the motor obstruction to item (GDP) discharge is high, despite the fact that GTP is in 10-overlap molar overabundance to GDP in the cytosol. Substitution of GDP by GTP in the dynamic site of a G protein is the turn-on flag that perpetually requires the help of a guanine nucleotide trade component, or GEF.

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Do you remember everything from yesterday's address? On the off chance that you say yes, you get a doughnut! If not, then you have to focus on the CREB story. Certainty: CREB: cAMP reaction component restricting protein. Ties to DNA at the CRE (cAMP Response Element) and initiates interpretation.

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What does CREB do? Point of interest papers in 1995 exhibited that cAMP-subordinate translation through CREB improve the arrangement of long haul memory (LTM)

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Can eating CREB make you keen? No But eating doughnuts can make you upbeat, and bliss is great mental wellbeing! Ideally doughnuts don't fortify initiation of CREB repressor qualities!

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cAMP is produced from ATP by a compound: adenylyl cyclase. Air conditioning is controlled by G proteins

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cAMP actuates at least one kinases. What are phosphatases?

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Activation of cAMP and Protein Kinase An additionally assume significant parts accordingly of liver to glucagon or epinephrine. Figure 15.7

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Thursday, IP3, Calcium and Receptor tyrosine kinases END

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Regulation of PIP2 and PIP3 Synthesis Green bolts indicate stimulatory impacts; blue bolts mean engineered pathways; red signifies inhibitory impact. Criticism inhibitory circle (1). Cross-talk between receptor flagging pathways (2). Nourish forward circle (3).

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Plasma Membrane Functions that Require . Function    Phosphoinositide     Possible Mechanism     Membrane Trafficking     Endocytosis     PIP2     Recruitment of AP2 to layer starting clathrin coating     PIP2     Uncoating of clathrin-covered vesicles, through synaptojanin-1-intervened PIP2 hydrolysis     Regulated exocytosis     PIP2     Recruitment of CAP protein to destinations of vesicle fusion     Membrane/Cytoskeletal Interface     Micovilli formation     PIP2     Activation of ERM proteins     Membrane connection to cytoskeleton     PIP2     Binding to gelsolin, profilin, other actin controller proteins     Phagocytosis     PIP2/PIP3     Regulation of ARF6, PLD and actin assembly     Cell Signaling     Protein kinase confinement and activation     PIP2/PIP3     Localization of PDK1 and PKB/Akt     PtdIns(3,4)P2/PIP3     Regulated limitation of Btk tyrosine kinase     Regulation of ARF GTPases     PIP2/PIP3     Localization of ARF6 trade factors     PIP3     ARFGAP localization     PIP2     Activation of ARF GAP     EGFR direction of film ruffling     PIP2     Actin reorganization