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Mostafa g protein

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Mostafa Askar
Mostafa Askar

G-proteins are signal transducing molecules involved in transmitting signals from extracellular receptors to intracellular effectors. They are made up of alpha, beta, and gamma subunits and can activate or inhibit downstream effectors like adenylate cyclase. Ligand binding to G-protein coupled receptors on the cell surface causes the activation of heterotrimeric G-proteins, which then activate second messenger molecules like cAMP, IP3, and DAG to propagate intracellular signaling cascades. These cascades regulate diverse cellular processes including gene expression, calcium signaling, and cell proliferation through the activation of proteins like protein kinase A, phospholipase C, and MAP kinases.

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Mostafa g protein
G-Protein G-ProteinTopology Topology Mostafa A.Askar Assistant Lecture Immunology&Cancer NCRRT,Cairo,Egypt
Signal transductions Signal transductions Divide into two categories: 1- Extracellular signaling Extracellular signaling molecules are synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules. As hydrophobic molecules such as steroids, retinoids, and thyroxine, spontaneously diffuse through the plasma membrane and bind to intracellular receptors
Overview of seven major classes of cell-surface receptors. In many signaling pathways, ligand binding to a receptor leads to activation of transcription factors in the cytosol, permitting them to translocate into the nucleus and stimulate (or occasionally repress) transcription of their target genes. Alternatively, receptor stimulation may lead to activation of cytosolic protein kinases that then translocate into the nucleus and regulate the activity of nuclear transcription factors. Some activated receptors, particularly certain G proteinC coupled receptors, also can induce changes in the activity of preexisting proteins (Figure 13-1) Next figure explain
(Figure 13-1)
Classification of Extracellular signaling
intracellular signaling molecules termed second messengers that cascade the signal pathway into nucleus. These molecules include ?cyclic AMP (cAMP), ?cyclic GMP (cGMP) ?1,2-diacylglycerol (DAG) ?inositol ?1,4,5-trisphosphate (IP3), whose structures are shown in Figure 13-7. ?Other important second messengers are Ca+2 and various inositol phospholipids, also called phosphoinositides, which are embedded in cellular membranes. ?Finally GTPase: the large group of intracellular superfamilly, act as in figure (M.A.1) 2- Intracellular signaling
figure (M.A.1) GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event.
G proteins were discovered when Alfred and Martin investigated stimulation of cells by adrenaline. They found that, when adrenaline binds to a receptor, the receptor does not stimulate enzymes directly. Instead, the receptor stimulates a G protein, which stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cAMP. For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine. G proteins discovery G proteins discovery Alfred G. Gilman Martin Rodbell
Definitions Definitions G proteins (guanine nucleotide-binding proteins) are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. It is the very large It is the very large group of cell surface receptors group of cell surface receptors (Extracellular) (Extracellular) that are coupled that are coupled to signal-transducing trimeric G proteins. All G proteinC to signal-transducing trimeric G proteins. All G proteinC coupled receptors (GPCRs) contain seven membrane-spanning coupled receptors (GPCRs) contain seven membrane-spanning regions with their N-terminal segment on the exoplasmic face regions with their N-terminal segment on the exoplasmic face and their C-terminal segment on the cytosolic face of the and their C-terminal segment on the cytosolic face of the plasma membrane plasma membrane (Figure 13-10). (Figure 13-10). The GPCR family includes The GPCR family includes receptors for numerous hormones and neurotransmitters, light receptors for numerous hormones and neurotransmitters, light activated receptors (rhodopsins) in the eye, and literally activated receptors (rhodopsins) in the eye, and literally thousands of odorant receptors in the mammalian nose. thousands of odorant receptors in the mammalian nose. G-Protein G-Protein
FIGURE 13-10 Schematic diagram of the general structure of G proteinCcoupled receptors. All receptors of this type have the same orientation in the membrane and contain seven transmembrane -helical regions (H1CH7), four extracellular segments (E1CE4), and four cytosolic segments (C1CC4). The carboxyl-terminal segment (C4), the C3 loop, and, in some receptors, also the C2 loop are involved in interactions with a coupled trimeric G protein.
G proteins are important signal transducing molecules in cells. In fact, diseases such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer, among other pathologies, are thought to arise due to derangement of G protein signaling. The human genome encodes roughly 950 G protein- coupled receptors, which detect photons (light), hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions. G-protein function G-protein function
G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptors and made up of alpha (), beta (), and gamma () subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha () subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction. Types of G protein signaling Types of G protein signaling
G-proteins, which consist of subunits and closely associated - subunits. The subunit is responsible for GTP and GDP binding and for GTP hydrolysis, whereas the and subunits are associated in a tightly linked -complex. Activation Activation Termination Termination
Www.ggene.Cn 15 G G i/o i/o G G s s G G q q G G 12 12 /13 /13 ? inhibition of cAMP production ? inhibition of Ca2+ channels ?activation of GIRK K+ channels G-protein subtypes ? increased synthesis of cAMP ?activation of Ca2+ and K+ channels ?activation of PLC leading to ?activation of PKC (DAG) ?intracellular Ca2+ release (IP3) ? mediates signalling between GPCRs and RhoA (GTPase) ? function under investigation
Activation of Gene Transcription by G Protein Coupled Receptors FIGURE 13-32 Activation of gene expression following ligand binding to Gs proteinCcoupled receptors. Receptor stimulation (1), leads to activation of PKA (2). Catalytic subunits of PKA translocate to the nucleus (3) and there phosphorylate and activate the transcription factor CREB (4). Phosphorylated CREB associates with the co-activator CBP/P300 (5) to stimulate various target genes controlled by the CRE regulatory element.
Mostafa g protein
Www.ggene.Cn 18 N C I I I I II I V V V I V II t h e s ig n a l t r a n s d u c t io n m a c h in e
Www.ggene.Cn 19 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s A r r t h e s ig n a l t r a n s d u c t io n m a c h in e T h e s e c a n b e c o n s id e r e d g e n e r a l m e c h a n is m s .
Www.ggene.Cn 20 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + A r r t h e s ig n a l t r a n s d u c t io n m a c h in e
Www.ggene.Cn 21 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 A r r t h e s ig n a l t r a n s d u c t io n m a c h in e M A P K
Www.ggene.Cn 22 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P A r r t h e s ig n a l t r a n s d u c t io n m a c h in e M A P K
Www.ggene.Cn 23 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r t h e s ig n a l t r a n s d u c t io n m a c h in e N a + /H + e x c h a n g e r M A P K
Www.ggene.Cn 24 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O t h e s ig n a l t r a n s d u c t io n m a c h in e N a + /H + e x c h a n g e r M A P K
Www.ggene.Cn 25 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O e N O S ? t h e s ig n a l t r a n s d u c t io n m a c h in e N a + /H + e x c h a n g e r M A P K
Www.ggene.Cn 26 N C I I I I II I V V V I V II t h e s ig n a l t r a n s d u c t io n m a c h in e G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O e N O S ? N P x x Y A R F R h o P L D N a + /H + e x c h a n g e r M A P K
Www.ggene.Cn 27 N C I I I I II I V V V I V II t h e s ig n a l t r a n s d u c t io n m a c h in e G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O e N O S ? N P x x Y A R F R h o P L D N a + /H + e x c h a n g e r M A P K G P C R s a r e t r u ly r e m a r k a b le s ig n a l t r a n s d u c t io n m a c h in e s . In s u m m a r y ... ..
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Mostafa g protein

  • 3. Signal transductions Signal transductions Divide into two categories: 1- Extracellular signaling Extracellular signaling molecules are synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules. As hydrophobic molecules such as steroids, retinoids, and thyroxine, spontaneously diffuse through the plasma membrane and bind to intracellular receptors
  • 4. Overview of seven major classes of cell-surface receptors. In many signaling pathways, ligand binding to a receptor leads to activation of transcription factors in the cytosol, permitting them to translocate into the nucleus and stimulate (or occasionally repress) transcription of their target genes. Alternatively, receptor stimulation may lead to activation of cytosolic protein kinases that then translocate into the nucleus and regulate the activity of nuclear transcription factors. Some activated receptors, particularly certain G proteinC coupled receptors, also can induce changes in the activity of preexisting proteins (Figure 13-1) Next figure explain
  • 7. intracellular signaling molecules termed second messengers that cascade the signal pathway into nucleus. These molecules include ?cyclic AMP (cAMP), ?cyclic GMP (cGMP) ?1,2-diacylglycerol (DAG) ?inositol ?1,4,5-trisphosphate (IP3), whose structures are shown in Figure 13-7. ?Other important second messengers are Ca+2 and various inositol phospholipids, also called phosphoinositides, which are embedded in cellular membranes. ?Finally GTPase: the large group of intracellular superfamilly, act as in figure (M.A.1) 2- Intracellular signaling
  • 8. figure (M.A.1) GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event.
  • 9. G proteins were discovered when Alfred and Martin investigated stimulation of cells by adrenaline. They found that, when adrenaline binds to a receptor, the receptor does not stimulate enzymes directly. Instead, the receptor stimulates a G protein, which stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cAMP. For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine. G proteins discovery G proteins discovery Alfred G. Gilman Martin Rodbell
  • 10. Definitions Definitions G proteins (guanine nucleotide-binding proteins) are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. It is the very large It is the very large group of cell surface receptors group of cell surface receptors (Extracellular) (Extracellular) that are coupled that are coupled to signal-transducing trimeric G proteins. All G proteinC to signal-transducing trimeric G proteins. All G proteinC coupled receptors (GPCRs) contain seven membrane-spanning coupled receptors (GPCRs) contain seven membrane-spanning regions with their N-terminal segment on the exoplasmic face regions with their N-terminal segment on the exoplasmic face and their C-terminal segment on the cytosolic face of the and their C-terminal segment on the cytosolic face of the plasma membrane plasma membrane (Figure 13-10). (Figure 13-10). The GPCR family includes The GPCR family includes receptors for numerous hormones and neurotransmitters, light receptors for numerous hormones and neurotransmitters, light activated receptors (rhodopsins) in the eye, and literally activated receptors (rhodopsins) in the eye, and literally thousands of odorant receptors in the mammalian nose. thousands of odorant receptors in the mammalian nose. G-Protein G-Protein
  • 11. FIGURE 13-10 Schematic diagram of the general structure of G proteinCcoupled receptors. All receptors of this type have the same orientation in the membrane and contain seven transmembrane -helical regions (H1CH7), four extracellular segments (E1CE4), and four cytosolic segments (C1CC4). The carboxyl-terminal segment (C4), the C3 loop, and, in some receptors, also the C2 loop are involved in interactions with a coupled trimeric G protein.
  • 12. G proteins are important signal transducing molecules in cells. In fact, diseases such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer, among other pathologies, are thought to arise due to derangement of G protein signaling. The human genome encodes roughly 950 G protein- coupled receptors, which detect photons (light), hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions. G-protein function G-protein function
  • 13. G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptors and made up of alpha (), beta (), and gamma () subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha () subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction. Types of G protein signaling Types of G protein signaling
  • 14. G-proteins, which consist of subunits and closely associated - subunits. The subunit is responsible for GTP and GDP binding and for GTP hydrolysis, whereas the and subunits are associated in a tightly linked -complex. Activation Activation Termination Termination
  • 15. Www.ggene.Cn 15 G G i/o i/o G G s s G G q q G G 12 12 /13 /13 ? inhibition of cAMP production ? inhibition of Ca2+ channels ?activation of GIRK K+ channels G-protein subtypes ? increased synthesis of cAMP ?activation of Ca2+ and K+ channels ?activation of PLC leading to ?activation of PKC (DAG) ?intracellular Ca2+ release (IP3) ? mediates signalling between GPCRs and RhoA (GTPase) ? function under investigation
  • 16. Activation of Gene Transcription by G Protein Coupled Receptors FIGURE 13-32 Activation of gene expression following ligand binding to Gs proteinCcoupled receptors. Receptor stimulation (1), leads to activation of PKA (2). Catalytic subunits of PKA translocate to the nucleus (3) and there phosphorylate and activate the transcription factor CREB (4). Phosphorylated CREB associates with the co-activator CBP/P300 (5) to stimulate various target genes controlled by the CRE regulatory element.
  • 18. Www.ggene.Cn 18 N C I I I I II I V V V I V II t h e s ig n a l t r a n s d u c t io n m a c h in e
  • 19. Www.ggene.Cn 19 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s A r r t h e s ig n a l t r a n s d u c t io n m a c h in e T h e s e c a n b e c o n s id e r e d g e n e r a l m e c h a n is m s .
  • 20. Www.ggene.Cn 20 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + A r r t h e s ig n a l t r a n s d u c t io n m a c h in e
  • 21. Www.ggene.Cn 21 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 A r r t h e s ig n a l t r a n s d u c t io n m a c h in e M A P K
  • 22. Www.ggene.Cn 22 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P A r r t h e s ig n a l t r a n s d u c t io n m a c h in e M A P K
  • 23. Www.ggene.Cn 23 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r t h e s ig n a l t r a n s d u c t io n m a c h in e N a + /H + e x c h a n g e r M A P K
  • 24. Www.ggene.Cn 24 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O t h e s ig n a l t r a n s d u c t io n m a c h in e N a + /H + e x c h a n g e r M A P K
  • 25. Www.ggene.Cn 25 N C I I I I II I V V V I V II G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O e N O S ? t h e s ig n a l t r a n s d u c t io n m a c h in e N a + /H + e x c h a n g e r M A P K
  • 26. Www.ggene.Cn 26 N C I I I I II I V V V I V II t h e s ig n a l t r a n s d u c t io n m a c h in e G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O e N O S ? N P x x Y A R F R h o P L D N a + /H + e x c h a n g e r M A P K
  • 27. Www.ggene.Cn 27 N C I I I I II I V V V I V II t h e s ig n a l t r a n s d u c t io n m a c h in e G e f f e c t o r s P P S R C g e n e r a l m e c h a n i s m s p P R O h o m e r S H 3 h o m e r IP 3 R C a 2 + p P R O G r h 2 N c k S H 3 In a D P D Z P L C P K C T R P C N H E R F A r r C c N O S a r g in in e N O e N O S ? N P x x Y A R F R h o P L D N a + /H + e x c h a n g e r M A P K G P C R s a r e t r u ly r e m a r k a b le s ig n a l t r a n s d u c t io n m a c h in e s . In s u m m a r y ... ..