Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 616 Agonist GPCR Trimeric G protein Receptor activated CYTOSOL Heterotrimeric G protein signaling Activated G protein dissociates IP 3 -gated Ca 2+ channel ENDOPLASMIC RETICULUM PIP 2 IP 3 Ca 2+ DAG Hydrolysis of PIP 2 to IP 3 and DAG Release of Ca 2+ FIGURE 14.21 G protein-mediated signal transduction follows a path of agonist to receptor to heterotrimeric G protein to effector to the effector's output. Both G and G subunits regulate distinct effectors. In the example shown here, G q regulates a phospholipase C- to produce two second messengers, diacyglycerol (DAG) and inositol-trisphosphate (IP 3 ). IP 3 triggers Ca2+ release from the endoplasmic reticulum. - output is a spectrum of cellular signals that is complex in both amplitude and kinetics. Because of their conserved parts list, G protein modules are well suited to initiating a wide variety of intracellular signals in response to diverse molecular inputs and can do so over a wide range of time scales (milliseconds to minutes). GPCRs are integral plasma membrane proteins composed of a bundle of seven hydrophobic membrane-spanning helices with an extracellular N terminus and cytosolic C terminus, as depicted in FIGURE 14.23. Based on the three-dimensional structure of rhodopsin and on copious biochemical and genetic data, it is likely that all GPCRs share the same basic mechanism of conformational activation and deactivation in response to activating ligands (see 14.5 Ligand binding changes receptor conformation). Binding of agonist ligand on the extracellular face of the receptor drives realignment of the helices to alter the structure of a binding site for the heterotrimeric G protein on the cytoplasmic face, and this altered conformation of the G proteinbinding surface promotes G protein activation. FIGURE 14.22 A portion of the G protein-mediated signaling network in macrophages highlights some of the complexity of interactions possible in such systems. Several receptors and G protein subunits are omitted. Where a named G protein is shown, its signaling output is probably mediated by its G subunit. Activation of any G protein also activates its G subunit, although Gmediated signaling is usually most prominent from G i trimers. In addition, several G proteins modulate the activities of others through poorly understood pathways. Only a small sampling of effectors is shown, and the only adaptive mechanism shown is GRK-catalyzed phosphorylation of receptors. Data from Paul Sternweis, Alliance for Cellular Signaling. Agonist C5a ISO PGE S1P UDP UTP PAF LPA GPCR G Protein Effector Partial G protein signaling network in mouse macrophages C5aR β 2 AR E2R EDG P2YR P2YR PAFR EDG Gi Gs G12 Gq Ad Cyc cAMP ATP PI 3- Kinase PIP 2 PLC-β G12 ?? PIP 3 DAG + IP 3 IP 2 + P i Phosphatase Inactivation mechanisms cAMP AMP PDE Ca2+ Ca2+ pump IP 3 R GRK 616 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 617 Structure of rhodopsin Heterotrimeric G protein structure CYTOPLASM MEMBRANE Retinal FIGURE 14.23 The figure shows the crystal structure of the GPCR rhodopsin. Each membrane-spanning helix is a different color; most structures on the cytoplasmic face are not shown. The retinal chromophore is shown within the helix bundle. GPCR sequence similarity separates the mammalian GPCRs into at least four structural families that are so diverse that there may be little sequence similarity among the classes. Within a family, similarity is greatest in the membrane-spanning helices, less in the interhelical loops, and least in the N- and C-terminal domains and in the cytoplasmic loop that connects spans five and six. Regardless, the generalizations about functional domains in receptors seem to hold true within different families. GPCRs frequently form dimers, occasionally heterodimers, and dimerization can be crucial for function. Structure generated from Protein Data Bank file 1F88. The heterotrimeric G proteins to which GPCRs are coupled are composed of a nucleotide-binding Gα subunit and a Gβγ subunit dimer, as illustrated in FIGURE 14.24. The structure of the trimer and each subunit is known for several states of activation and in complex with several interacting proteins. A Gαβγ heterotrimer is named according to its α subunit, which largely defines the G protein’s selectivity among receptors. Each subunit also regulates a distinct group of effector proteins. Gα subunits are globular, two-domain proteins of 38-44 kDa. The GTP-binding domain belongs to the GTP-binding protein superfamily that includes the small, monomeric G proteins (such as Ras, Rho, Arf, Rab; see 14.23 Small, monomeric GTP-binding proteins are multiuse switches) as well as the GTP-binding translational initiation and elongation factors. A second domain modulates GTP binding and hydrolysis. Gα subunits are only slightly hydrophobic, but they are predominantly membrane-associated FIGURE 14.24 The structure of the nonactivated G i heterotrimer, the G protein that is responsible for inhibition of adenylyl cyclase and for most G-mediated signaling, is shown with each subunit colored as shown. GDP is shown bound to the G i subunit. Structure generated from Protein Data Bank file 1GP2. G protein Gs Golf Gi (3) Go Gz Ggus Gt (2) Gq (4) G 12 G 13 Adenylyl cyclase EFFECTOR PROTEIN K+channel, PI 3-kinase Other cation channel Rho GEF G protein targets Stimulated Cyclic GMP phosphodiesterase Phospholipase-Cβ Inhibited Adenylyl cyclase FIGURE 14.25 G protein-regulated effectors do not share structural similarities. They may be ion channels or membrane spanning enzymes in the plasma membrane, peripheral proteins on the inner face of the membrane, or fundamentally soluble proteins that can bind to G subunits. The chart shows the major groups of G proteins, sorted according to sequence similarity, and some of the effectors that they are known to regulate. because of constitutive N-terminal fatty acylation and because they bind to the membraneattached Gβγ subunits. Mammals have 16 Gα genes that are grouped in subfamilies according to similar sequence and function (e.g., s, i, q, and 12). These subfamilies are listed in FIGURE 14.25. Gβ and Gγ subunits associate irreversibly soon after translation to form stable Gβγ dimers, which then associate reversibly with a Gα. Gβ subunits are 35 kDa proteins composed of seven 14.20 G protein signaling modules are widely used and highly adaptable 617
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Principles of cell signaling - UT Southwestern

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