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The Heterotrimeric G Proteins

The heterotrimeric G-proteins are the specific reaction partners in signal transmission via 7-helix transmembrane receptors, which is why these receptors are also known as G-protein-coupled receptors. From the G-protein, the signal is then passed on to the effector protein next in the sequence (review Hepler and Gilman, 1992 Neer, 1995). [Pg.192]

A common structural feature of the G-proteins is their construction from three sub-imits (Fig. 5.14), a large a-subimit of 39-46 kDa, a P-subimit of 37 kDa and a y-subimit of 8 kDa. The a-subunit has a binding site for GTP or GDP and carries the GTPase activity. The P- and y-subimits exist as a tightly associated complex and are active in this form. All three subimits show great diversity, so that at least 20 different genes for a-subimits, 5 for P-subunits and 12 for y-subimits are known in mammals. Some G-pro-teins are ubiquitous, whereas others only occur in specialized tissue. [Pg.192]

Specificity of the switch fimction is mostly determined by the a-subunit the a-sub-imit carries out the specific interaction with the receptors preceding in the signal chain and with the subsequent effector molecules. The Py-complex may also be involved in signal transmission to the effector proteins. [Pg.192]

Adenylyl cyclase Phospholipase A2 K channels ( . ) Phospholipase C 5 p - adrenergic receptor [Pg.203]

A characteristic of a-subunits of the Gs subfamily is that they are inhibited by cholera toxin (see Section 5.5.2). The members of the Gs subfamily are activated by hormone receptors, by odor receptors and by taste receptors. Gs-proteins mediate, e.g., signal transmission by type fl adrenaline receptors and that by glucagon receptors. During perception of taste, the taste receptors are activated, and these then pass the signal on via the olfactory G protein G0if. Perception of sweet taste is also mediated via a Gs-protein. Transmission of the signal further involves an adenylyl cyclase in all cases, the activity of which is stimulated by the Gs-proteins. [Pg.204]


It is appreciated that certain ion channels appear to be directly regulated by various G-proteins [126]. The cardiac and skeletal muscle L channels appear to be capable of being directly activated by Gs (the heterotrimeric G-protein that stimulates adenylate cyclase), in a manner that appears to be independent of second messenger... [Pg.331]

The phospholipases (PLC) isozymes cleave the phosphodiester bond in phos-phatidyl-inositol-4,5-bisphosphate (PIP2) releasing two second messenger molecules inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) as shown before. The /1-isozyme are controlled by the Ga or G y subunits of the heterotrimeric G-proteins coupled to surface receptors. The y-isozymes are substrates for tyrosine kinases, such as growth factors. [Pg.196]

Figure 6.2. Structure of heterotrimeric G-proteins. The generalised structure of the a-, /3-, and y-subunits of the heterotrimeric G-proteins and their organisation in the plasma membrane are shown. Figure 6.2. Structure of heterotrimeric G-proteins. The generalised structure of the a-, /3-, and y-subunits of the heterotrimeric G-proteins and their organisation in the plasma membrane are shown.
B. Signaling is initiated by binding of an extracellular ligand, which produces a conformational change in the receptor that allows it to bind to the heterotrimeric G protein. [Pg.201]

Figure 14-1. Signaling via G protein-coupled receptors. Ligand binding to its cell-surface receptor initiates interaction of the receptor with the heterotrimeric G protein for which it is specific. A conformational change in the G protein brought about by binding of the ligand-receptor complex promotes exchange of GDP for GTP. The activated Gd-GTP dissociates from the Gp complex and both can interact with effectors, which carry on the signal to the mechanism that implements the cellular response. Figure 14-1. Signaling via G protein-coupled receptors. Ligand binding to its cell-surface receptor initiates interaction of the receptor with the heterotrimeric G protein for which it is specific. A conformational change in the G protein brought about by binding of the ligand-receptor complex promotes exchange of GDP for GTP. The activated Gd-GTP dissociates from the Gp complex and both can interact with effectors, which carry on the signal to the mechanism that implements the cellular response.
One of the major adaptors is the GRB2-SOS complex, which upon docking to the phosphorylated receptor, binds the small G protein Ras and activates it by GDP-GTP exchange in a manner analogous to the heterotrimeric G proteins. [Pg.207]

Palmitoylation is, after myristoylation, the most common modification of the a-sub-rmit of the heterotrimeric G-proteins (see chapter 5). The a-subunit of G-proteins can be lipidated in a two-fold marmer, with a myristoic acid and a pahnitoic acid anchor at the N-terminus. It appears in this case that two lipid anchors are necessary to mediate a stable association of the protein with the membrane. The lipidation of cytoplasmic protein tyrosine kinase also includes both myristoylation and palmitoylation. H-Ras protein also requires, apart from C-terminal farnesylation (see below), a pahnitoyl modification in order to bind to the plasma membrane. In all mentioned examples the fatty acid anchors play an essential role in the signal transduction. [Pg.144]

The mechanism by which the activated receptor talks to the G-protein is only partially understood. Generally, the switch function of the receptor is considered in terms of allosteric conformational changes of the 7-hehx membrane bimdle (review Bourne, 1997). According to this representation, changes in the structure of the transmembrane bimdle are passed on to the cytoplasmic loops of the receptor. Communication with the a-subunit of the heterotrimeric G-protein takes place via these loops. [Pg.183]

The heterotrimeric G-protein, which exists as the inactive GDP form, now binds via its a-subunit to the activated receptor and is activated itself. An exchange of GDP for GTP takes place and the Pysubunit of the G-protein dissociates (see 5.5.3). Once the G-protein is activated, it frees itself from the complex with the receptor, which either returns to its inactive ground state or activates further G-proteins. [Pg.183]

Acceleration of the dissociation of GDP increases the proportion of the active form. The rate of dissociation of GDP may be increased by specific proteins. These proteins are known as guanine nucleotide exchange factors (GEF). For the heterotrimeric G-proteins, the agonist-boimd, activated receptor is the exchange factor. [Pg.189]

The superfamily of GTPases with their more than hundred members are divided by sequence homologies, molecular weight and subimit structure into further (super)fa-milies. These are the families of the heterotrimeric G-proteins, the Ras/GTPase superfamily and the family of initiation and elongation factors (Fig. 5.13). [Pg.191]

The heterotrimeric G-proteins are built of three subunits, with the GTPase activity localized on the largest subunit (see 5.5). The members of the Ras/GTPases, in contrast, are monomeric proteins with a molecular weight of ca.20 kDa (see Chapter 9). [Pg.191]

Fig. 5.14. Structure and activation of the heterotrimeric G-proteins. Reception of a signal by the receptor activates the G-protein, which leads to exchange of bound GDP for GTP at the a-sub-unit and to dissociation of the pycomplex. Further transmission of the signal may take place via Ga-GTP or via the Py-complex, which interact with corresponding effector molecnles. The a- and y-subunits are associated with the cell membrane via lipid anchors. Signal reception and signal transmission of the heterotrimeric G-proteins take place in close association with the cell membrane. This point is only partially shown in the fignre. Fig. 5.14. Structure and activation of the heterotrimeric G-proteins. Reception of a signal by the receptor activates the G-protein, which leads to exchange of bound GDP for GTP at the a-sub-unit and to dissociation of the pycomplex. Further transmission of the signal may take place via Ga-GTP or via the Py-complex, which interact with corresponding effector molecnles. The a- and y-subunits are associated with the cell membrane via lipid anchors. Signal reception and signal transmission of the heterotrimeric G-proteins take place in close association with the cell membrane. This point is only partially shown in the fignre.
Table 5.1. Classification of the heterotrimeric G-proteins according to the a-subunits... Table 5.1. Classification of the heterotrimeric G-proteins according to the a-subunits...
Like all regulatory GTPases, the heterotrimeric G-proteins nm through a cyclical transition between an inactive, GDP-boimd form and an active, GTP-boimd form. Fig. 5.16 sketches the different functional states and the role of the individual subunits. [Pg.196]

Fig. 5.16. Functional cycle of the heterotrimeric G-proteins. a) The G-proteins exist in the ground state as a heterotrimeric complex (G GDP) (Py)- b) The activated receptor binds to the inactive heterotrimeric complex of the G-protein and leads to dissociation of the bound GDP and the Pyeomplex. c) Binding of GTP to the empty G -subunit transforms the latter into the active G GTP state. G GTP interacts with an effector molecule in the sequence El and activates the latter for further signal transmission. The released Py-complex may also take part in signal conduction by binding to a corresponding effector molecule E2 and activating the latter for further signal conduction, d) Hydrolysis of the bound GTP terminates the signal transduction via the a-subunit. Fig. 5.16. Functional cycle of the heterotrimeric G-proteins. a) The G-proteins exist in the ground state as a heterotrimeric complex (G GDP) (Py)- b) The activated receptor binds to the inactive heterotrimeric complex of the G-protein and leads to dissociation of the bound GDP and the Pyeomplex. c) Binding of GTP to the empty G -subunit transforms the latter into the active G GTP state. G GTP interacts with an effector molecule in the sequence El and activates the latter for further signal transmission. The released Py-complex may also take part in signal conduction by binding to a corresponding effector molecule E2 and activating the latter for further signal conduction, d) Hydrolysis of the bound GTP terminates the signal transduction via the a-subunit.
The switch fimction of the a-subunit of the heterotrimeric G-proteins is foimded on the change between an active G -GTP confirmation and an inactive Ga-GDP conformation. The structural difference between the two conformations was explained for the transducin, G, , by crystallization and structural characterization of the inactive GDP form and the active GTPyS form (Lambright et al., 1994). The structures of both forms of Gt, are shown in Fig. 5.19. [Pg.202]

Gt,a is made up of two domains, a GTPase domain and a helical domain. The GTPase or G-domain indicates that Gt, is a member of the superfamily of regulatory GTPases. In addition, G, possesses a helical domain, which represents a characteristic feature of the heterotrimeric G-proteins. The nucleotide binding site is in a cleft between the two domains. It is assumed that the presence of the helical domain is the reason that bound nucleotide dissociates only very slowly from transducin and that the activated receptor is therefore necessary to initiate the GDP/GTP exchange. [Pg.202]

Fig. 5.19. GTP and GDP structures of transducin. The Ga,t subunit of transducin possesses—in contrast to Ras protein and to other small regulatory GTPases —an a-hehcal domain that hides and closes the G-nucleotide binding pocket. The conformational changes that accompany the transition from the inactive G t GDP form (a) into the active G t GTP form (b), are restricted to three structural sections that are known as switches I, II and III. Switch I includes the link of the a-helical domain with P2, switch II affects in particular hehx a2, and switch III, the pS—a3 loop. Switch III includes a sequence that is characteristic for the a-subunits of the heterotrimeric G-proteins. The conformational changes of switches II and III affect structural sections that are assumed to be binding sites for the effector molecule adenylyl cyclase (AC) and the y-subunit of cGMP-dependent phosphodiesterase (PDEy), based on mutation experiments and biochemical investigations. MOLSKRIPT representation according to Krauhs, (1991). Fig. 5.19. GTP and GDP structures of transducin. The Ga,t subunit of transducin possesses—in contrast to Ras protein and to other small regulatory GTPases —an a-hehcal domain that hides and closes the G-nucleotide binding pocket. The conformational changes that accompany the transition from the inactive G t GDP form (a) into the active G t GTP form (b), are restricted to three structural sections that are known as switches I, II and III. Switch I includes the link of the a-helical domain with P2, switch II affects in particular hehx a2, and switch III, the pS—a3 loop. Switch III includes a sequence that is characteristic for the a-subunits of the heterotrimeric G-proteins. The conformational changes of switches II and III affect structural sections that are assumed to be binding sites for the effector molecule adenylyl cyclase (AC) and the y-subunit of cGMP-dependent phosphodiesterase (PDEy), based on mutation experiments and biochemical investigations. MOLSKRIPT representation according to Krauhs, (1991).
Fig. 5.20. Membrane anchor of the heterotrimeric G-proteins. The lipid anchoring in the system of G-protein-conpled receptors and the corresponding G-proteins is shown. In the figure, it is assumed that the hpid anchors are located in the membrane. A possible involvement of the hpid anchor in protein-protein interactions is not shown. The G-protein-coupled receptor carries a pal-mitoic add anchor at the C-terminus. The a-subunit of the heterotrimeric G-protein is assodated with the membrane via a myristoic acid anchor at the N-terminus, whilst the y-subunit of the Py-complex uses a prenyl residue as a membrane anchor. Fig. 5.20. Membrane anchor of the heterotrimeric G-proteins. The lipid anchoring in the system of G-protein-conpled receptors and the corresponding G-proteins is shown. In the figure, it is assumed that the hpid anchors are located in the membrane. A possible involvement of the hpid anchor in protein-protein interactions is not shown. The G-protein-coupled receptor carries a pal-mitoic add anchor at the C-terminus. The a-subunit of the heterotrimeric G-protein is assodated with the membrane via a myristoic acid anchor at the N-terminus, whilst the y-subunit of the Py-complex uses a prenyl residue as a membrane anchor.
Fig. 9.1. The Ras protein as a central switching station of signaling pathways. A main pathway for Ras activation is via receptor tyrosine kinases, which pass the signal on via adaptor proteins and guanine nucleotide exchange factors to the Ras protein. Activation ofRas protein can also be initiated via G-protein-coupled receptors and via transmembrane receptors with associated tyrosine kinase activity. The membrane association of the Ras protein (see Fig. 9.6) is not shown for clarity. In addition, not aU signahng pathways that contribute to activation of the Ras protein are shown, nor are all effector reactions. Py omplex of the heterotrimeric G proteins GAP GTPase activating protein GEF guanine nucleotide exchange factor. Fig. 9.1. The Ras protein as a central switching station of signaling pathways. A main pathway for Ras activation is via receptor tyrosine kinases, which pass the signal on via adaptor proteins and guanine nucleotide exchange factors to the Ras protein. Activation ofRas protein can also be initiated via G-protein-coupled receptors and via transmembrane receptors with associated tyrosine kinase activity. The membrane association of the Ras protein (see Fig. 9.6) is not shown for clarity. In addition, not aU signahng pathways that contribute to activation of the Ras protein are shown, nor are all effector reactions. Py omplex of the heterotrimeric G proteins GAP GTPase activating protein GEF guanine nucleotide exchange factor.
In the high resolution crystal structure of the GTP form of Ras protein, a tightly bound water molecule is visible located in an optimal position for nucleophilic attack on the y-phosphate (Wittinghofer et al., 1993). The water molecule is fixed in a defined position by H-bridges with GIn61 and Hir35. As described in 5.4.4 for the a-subunits of the heterotrimeric G-proteins, GTP hydrolysis takes place by an in-line attack of the nucleophilic water molecule on the y-phosphate, for which a pentagonal, bipyramidal transition state is postulated. [Pg.330]

The ion channel and the receptor are separate signal elements here, with functional states coupled via the heterotrimeric G-protein. The mechanism of opening of ion channels by G-proteins is unknown. [Pg.486]


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