Mechanisms and Pathways of Heterotrimeric G Protein Signaling
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Table of contents
- Contentsv
- Prefacevii
- Chapter 1: Structural Basis of Effector Regulation and Signal Termination in Heterotrimeric Galpha P1
- I. Introduction and Scope3
- II. A Selective Survey of Galpha Protein Structure and Function5
- III. Mechanisms of Effector Recognition and Regulation by GalphabullGTP9
- A. A Common Galpha:Effector Interface11
- B. Functional Consequences of Galpha:Effector Binding15
- IV. Signal Termination: The Mechanism of GTP Hydrolysis and Conformational Deactivation23
- A. Structure of the Ground State for GTP Hydrolysis25
- B. Reaction Trajectory for GTP Hydrolysis28
- V. Signal Termination Through GAPs and Effector GAP Domains38
- A. Deactivation of Galphaq by PLCbeta39
- B. RGS GAPs41
- C. Synergy Between RGS and Effector Domains46
- D. Deactivation of Galpha 13 by the alphaGAP Element of p115RhoGEF47
- VI. Conclusions51
- Acknowledgments52
- References52
- Chapter 2: How do Receptors Activate G Proteins?67
- I. Introduction67
- A. Structure of Heptahelical Receptors68
- B. Heterotrimeric G Protein Structure70
- II. Toward a Model of the Receptor-G Protein Complex72
- A. Structural Determinants of Receptor-G Protein Specificity72
- B. Point to Point Interactions Between Receptors and G Proteins77
- C. Current Approaches to Modeling the Receptor-G Protein Complex77
- III. Molecular Basis for G Protein Activation80
- IV. Summary and Conclusions84
- References86
- Chapter 3: Some Mechanistic Insights into GPCR Activation from Detergent-Solubilized Ternary Complex95
- I. Perspectives96
- II. Survey of Experimental Approaches and Representative Data99
- A. Flow Cytometric Approaches to Assess GPCR Function In Vivo99
- B. Rapid Mix Flow Cytometry100
- C. Modular Assembly of Molecular Complexes on Beads100
- III. Analysis of Soluble Receptor Ternary Complex Assemblies104
- A. General Considerations104
- B. Simple Ternary Complex Model: General Considerations105
- C. Application of Ternary Complex Model108
- D. Landscapes of G-Bead Assemblies Based on Application of Experimentally Derived Binding Constants109
- E. Ternary Complex Analysis of Soluble Receptor Assemblies111
- F. Are Unique Conformational Changes in Receptors Elicited by Interactions with Ligands Resulting in115
- IV. Guanine Nucleotide Activation of Ternary Complex: Some Dynamic Aspects of Structure and Reactivi117
- A. General Considerations117
- B. Structural Studies118
- C. Some Dynamic Aspects of GPCR Activation119
- D. Modular Disassembly of the Ternary Complexes: Guanine Nucleotide Activation Causes the Rapid Sepa121
- E. GDP Activity?125
- F. Galpha Subunit Dissociation?126
- G. Outlook127
- Acknowledgments128
- References128
- Chapter 4: Activation of G Protein-Coupled Receptors137
- I. Introduction138
- II. Structural and Mechanistic Homology Among GPCRs140
- A. Rhodopsin as a Structural Model for GPCRs140
- B. GPCRs Activated by Diffusible Agonists141
- C. GPCR Oligomers142
- III. Conformational States143
- A. Basal Activity and Ligand Efficacy144
- B. Multiple Agonist-Specific States145
- C. Defining the "Active State"146
- IV. Activation by Agonists148
- A. Insights from Constitutively Active Mutants148
- B. Molecular Switches150
- C. Activation of Molecular Switches by Ligands153
- D. Agonist Binding and Activation Is a Multistep Process155
- E. The beta2AR as a Model System for Ligand Binding and Activation: Biophysical Analysis of Agonist-155
- V. Concluding Remarks159
- References159
- Chapter 5: Kinetic Analysis of G Protein-Coupled Receptor Signaling Using Fluorescence Resonance Ene167
- I. Introduction167
- II. Assays and Methods170
- A. Principle of the Assays170
- B. Construction and Expression of Fluorescent Receptor and G Protein Constructs176
- C. Microscopic FRET Measurements and Imaging177
- III. Results and Discussion179
- A. Agonist Binding179
- B. Receptor Activation180
- C. Receptor-G Protein Interaction182
- D. G Protein Activation183
- IV. Conclusions184
- Acknowledgments185
- References185
- Chapter 6: Regulation of Rho Guanine Nucleotide Exchange Factors by G Proteins189
- I. Introduction190
- A. Intrinsic Mechanisms of G Proteins190
- B. Regulation of Rho Proteins by Heterotrimeric G Proteins193
- II. RGS-RhoGEFs193
- A. Discovery and Relationships193
- B. The RGS Domain and GTPase Activity196
- C. The DH and PH Domains: Structure and Relative Activities200
- III. Mechanisms of Regulation201
- A. Direct Regulation of GEF Activity by G12 and G13201
- B. Indirect Regulation of RGS-RhoGEF Activity203
- C. Role of the C-Terminus in Oligomerization and Regulation of In Vivo Activity205
- D. Specificity of Regulation by G Proteins206
- E. Regulation of RGS-RhoGEFs by Phosphorylation208
- F. Function of the PDZ Domain209
- G. Expression of PDZ-RhoGEFs213
- IV. Physiological Function of the RGS-RhoGEFs213
- A. Pathway Specificity214
- B. Regulation in Hematopoietic Cells214
- C. Interactions with Other Proteins216
- Acknowledgments221
- References221
- Author Index229
- Subject Index247
This volume in the Advances in Protein Chemistry series features cutting-edge articles on topics in protein chemistry. This volume includes chapters on the structural basis of effector regulation and signal termination in heterotrimeric GƒÑƒnƒnproteins; How do receptors activate G proteins; Some mechanistic insights into GPCR activation from detergent solubilized ternary complexes on beads; Activation of G protein coupled receptors; Kinetic analysis of g-protein-coupled receptor signaling using fluorescence resonance energy transfer in living cells; Regulation of Rho Guanine Nucleotide Exchange Factors (RhoGEFs) by G proteins.