Functioning of Transmembrane Receptors in Signaling Mechanisms (eBook)

Front Cover 1
Functioning of Transmembrane Receptors in Cell Signaling 4
Copyright Page 5
Editorial Advisory Board 6
Contents 8
Preface 12
Contributors 14
Section A: Overview 18
Chapter 1: Transmembrane Receptors and Their Signaling Properties 20
Origins of Cell Signaling Research 20
Transmembrane Receptors 21
Focus and Scope of this Volume 23
References 24
Section B: Biophysical Principles and General Properties 26
Chapter 2: Structural and Energetic Basis of Molecular Recognition 28
Introduction 28
Principles of Binding 28
Non-Specific Association with Membrane Surfaces 29
Protein – Protein Interactions 29
Prospects 29
References 30
Chapter 3: Free Energy Landscapes in Protein – Protein Interactions 32
Thermodynamics of Protein – Protein Interactions 32
Interaction Kinetics 33
Dissociation of a Protein Complex 35
The Modular Structure of Protein – Protein Binding Sites 35
Interaction Between Membrane Anchored Proteins 36
Summary 37
References 37
Chapter 4: Molecular Sociology 40
Transmembrane Signaling Paradigms 40
Structural Basis of Protein – Protein Recognition 43
Conclusion 44
References 44
Chapter 5: FRET Analysis of Signaling Events in Cells 46
Introduction 46
Fluorescent Probes for Fret 46
Fret Detection Techniques 47
Conclusions and Prospects 49
References 49
Chapter 6: Structures of Serine/Threonine and Tyrosine Kinases 52
Introduction 52
Structural Features of Serine/Threonine and Tyrosine Kinases 52
Regulation of Serine/Threonine and Tyrosine Kinase Activity 53
Prospects 55
Acknowledgements 55
References 55
Chapter 7: Large-Scale Structural Analysis of Protein Tyrosine Phosphatases 58
Overview 58
Structural Coverage of the Family 58
Structural Features 58
A Shared Catalytic Mechanism 60
Receptor Dimerization 62
Endnote 62
References 63
Chapter 8: Transmembrane Receptor Oligomerization 64
Introduction 64
Tyrosine Kinase-Containing Receptors 65
Cytokine Receptors 65
Guanylyl Cyclase-Containing Receptors 67
Serine/Threonine Kinase-Containing Receptors 67
Tumor Necrosis Factor Receptors 67
Heptahelical Receptors (G-Proteincoupled Receptors) 68
Concluding Remarks 68
References 68
Section C: Major Receptor Families 70
Part 1: Receptor Tyrosine Kinases 72
Chapter 9: Protein Tyrosine Kinase Receptor Signaling Overview 74
Introduction 74
PTK Subfamilies 74
Mechanism of Activation 75
Control of PTK Receptor Activity 78
Cross-Talk Between Signaling Pathways 78
PTK Receptors and Disease 79
Acknowledgements 80
References 80
Chapter 10: Receptor Tyrosine Kinase Signaling and Ubiquitination 82
Introduction 82
The Ubiquitin Conjugation System 82
RTK Signaling and Endocytosis are Molecularly Linked 82
Ubiquitination in RTK Endocytosis 83
Ubiquitination of Effector Proteins in RTK Signaling 84
Concluding Remarks and Future Perspectives 84
Acknowledgements 84
References 85
Chapter 11: Insulin Receptor Complex and Signaling by Insulin 86
Introduction 86
Insulin Receptor Domain Structure 86
Binding Determinants of the Insulin Receptor 87
Insulin Signaling to Glucose Transport 88
Acknowledgements 90
References 90
Chapter 12: Structure and Mechanism of the Insulin Receptor Tyrosine Kinase 92
Introduction 92
Protein Recruitment to the Activated Insulin Receptor 93
Prospects 97
Acknowledgements 97
References 97
Chapter 13: IRS-Protein Scaffolds and Insulin/IGF Action in Central and Peripheral Tissues 100
Introduction 100
Insulin, Igfs, and their Receptors 100
Insulin Receptor Substrates 101
Dysregulation of IRS-Protein Signaling 104
Summary and Perspectives 107
References 107
Chapter 14: The Epidermal Growth Factor Receptor Family 112
Introduction 112
Structure and Activation of ERBB Receptors and their Ligands 112
ERBB-Induced Signaling Pathways 114
Specificity of Signaling Through the ERBB Network 114
Attenuation of the ERBB Signaling Network 115
ERBB Proteins and Pathological Conditions 116
Acknowledgements 117
References 117
Chapter 15: Epidermal Growth Factor Kinases and their Activation in Receptor Mediated Signaling 120
Introduction 120
EGFR Signaling Network Pathways 121
Structural Biology of Receptor Fragments 122
Conformations of the ECD Fragments of ErbB Receptors 122
Kinase Domain Fragment Structures 122
Biophysical Studies of ErbB Activation at the Cell Surface 123
ErbB Receptors Exist as Predominantly Pre-Formed Dimers in Cells 123
Beyond Dimers: A Ligand-Induced EGFR Tetramer is Formed During Activation 123
Activation-Dependent Higher-Order ErbB Oligomers in Cancer Cells 124
New Paradigm in ErbB Activation and Signaling 125
References 125
Chapter 16: Role of Lipid Domains in EGF Receptor Signaling 128
Introduction 128
Studying Lipid Rafts 129
Localization of the EGF Receptor in Lipid Rafts 129
Rafts and EGF Receptor-Mediated Signaling 130
The EGF Receptor and Caveolin 131
References 132
Chapter 17: Signaling by the Platelet-Derived Growth Factor Receptor Family 134
Platelet-Derived Growth Factor Isoforms 134
Physiological Function of PDGF 134
Activation of Platelet-Derived Growth Factor Receptors and Regulation of Kinase Activity 135
Interaction of the PDGF Receptors with Downstream Signal Transduction Molecules 135
Regulation and Modulation of PDGF Receptor Signaling 137
Conclusions 139
Acknowledgements 139
References 139
Chapter 18: The Fibroblast Growth Factor (FGF) Signaling Complex 142
Introduction 142
FGF Polypeptides 142
FGFR Tyrosine Kinases 143
Heparan Sulfate and Klothos 143
The Oligomeric FGF – FGFR – HS Signaling Complex 144
Intracellular Signal Transduction by the FGFR Complex 145
References 146
Chapter 19: The Mechanism of NGF Signaling Suggested by the p75 and TrkA Receptor Complexes 150
Introduction 150
Neurotrophins 150
NGF – TrkA Complexes 152
NGF – p75 NTR Complexes 153
Neurotrophin Signaling Excursions 154
Prospects for Ternary Receptor Complexes 155
Neurotrophin Therapeutics 155
References 155
Chapter 20: The Mechanism of VEGFR Activation by VEGF 160
Structural Characterization of VEGF Family Members 160
Structural Characterization of VEGFRs 161
Pdgfr and Analogies to VEGFRs 162
VEGF Co-Receptors: Neuropilins 163
Conclusion 163
References 164
Chapter 21: Mechanisms and Functions of Eph Receptor signaling 166
Introduction 166
Eph/Ephrin Protein Structures and Signaling Concepts 166
Regulation of Eph/Ephrin Signaling Activity 168
Disruption of Cell – Cell Contacts and Internalization of Signaling Complexes 168
Eph (Forward) Signaling 168
Ephrin (Reverse) Signaling 169
Cross-Talk with Other Signal Pathways 169
Eph/Ephrin Facilitated Cell - Cell Communication During Vertebrate Development 170
Ephs in Oncogenesis: De-Regulated Cell Positioning During Invasion and Metastasis 170
References 171
Part 2: Cytokine Receptors 174
Chapter 22: Overview of Cytokine Receptors 176
Chapter 23: Cytokine Receptor Signaling 178
Introduction 178
Generation of High-Affinity Cytokine – Receptor Complexes 178
Architecture of Extracellular Domain 178
Receptor Signaling-Utilizing EPO-R as a Model 180
Activation of the JAK Tyrosine Kinases 180
JAK1 181
JAK2 181
JAK3 181
TYK2 182
Recruitment and Activation of STAT Transcription Factors 182
STAT1 182
STAT2 182
STAT3 184
STAT4 184
STAT5 184
STAT6 185
Participation of the Phoshatidylinositol 3' Kinase Pathway in Cell Survival Signaling 185
ERK, JNK and P38 are All Activated Downstream of Cytokine Receptor Engagement 185
Negative Regulation 186
Developmental Regulation of the Cytokine Signaling Pathway 186
Involvement of the Cytokine Signaling Pathway in Human Disease 187
Concluding Remarks 188
Acknowledgements 188
References 190
Chapter 24: Growth Hormone and Prolactin Family of Hormones and Receptors: The Structural Basis for Receptor Activation and Regulation 194
Introduction 194
The Growth Hormone Family of Hormones and Receptors 194
Triggering GH and PRL Receptor Activation: Revision to the Dogma 194
An Unanticipated Role for Cytokine Hormones as Transcriptional Enhancers 195
Structural Basis for Receptor Homodimerization 196
Hormone Specificity and Cross-Reactivity Determines Physiological Roles 198
Concluding Remarks 198
References 199
Chapter 25: Erythropoietin Receptor as a Paradigm for Cytokine Signaling 202
Introduction 202
Structural Studies on EPOR 202
Biochemical Studies Supporting Preformed Dimers 205
Other Cytokine Receptor Superfamily Members 207
Conclusions 207
Acknowledgements 208
References 208
Chapter 26: Structure of IFN. and its Receptors 210
References 212
Part 3: G Protein-Coupled Receptors 214
Chapter 27: Structures of Heterotrimeric G Proteins and their Complexes 216
Introduction 216
G Subunits 216
G-Effector Interactions 219
GTP Hydrolysis by G and its Regulation by GAPs 219
Gß. Dimers 221
Receptor-Independent Regulators of G Protein Activation 222
Ga – GPCR Interactions 222
References 223
Chapter 28: G Protein-Coupled Receptor Structures 226
Introduction 226
Classification 226
Basic Concept of GPCR Heterotrimeric G Proteins
Models for Receptor Activation 230
Structures of Extracellular Domains of GPCRs 230
Structures Probing the Inactive State(S): Ligand Entry, Binding, and Modes for Activity Blocking 230
Structure of Active State(S) 232
Acknowledgements 234
References 234
Chapter 29: Heterotrimeric G-Protein Signaling at Atomic Resolution 236
Introduction 236
Architecture and Switching Mechanism of the Ga Subunits 236
Insight into the GTP Hydrolytic Mechanism from an Unexpected Transition State Mimic 237
Gß. with and without Ga 237
Phosducin and Gß. 238
GSa and Adenylyl Cyclase 238
Filling in the Gap 239
Visual Fidelity 239
What Structures May Follow 239
References 239
Chapter 30: Structure and Function of G-Protein-Coupled Receptors: Lessons from Recent Crystal Structures 242
Introduction 242
Recent Advances in Structural Studies of G-Protein-Coupled Receptors 242
Crystal Structures of Human ß2AR 244
Understanding Ligand Binding Specificity in GPCRs 245
Structural Basis of the Active State 245
References 246
Chapter 31: Chemokines and Chemokine Receptors: Structure and Function 248
Introduction 248
Chemokine Structure and Function 248
Chemokine Receptors 250
References 251
Chapter 32: The ß2 Adrenergic Receptor as a Model for G-Protein-Coupled Receptor Structure and Activation by Diffusible Hormone 254
Introduction 254
A Model System for GPCRs Recognizing Diffusible Ligands 254
Conformational States on the Pathway to Activation 255
Crystal Structures of the Human ß2AR 256
Comparison to the Structure of Rhodopsin 256
Mechanism of Agonist-Induced Activation 257
References 259
Chapter 33: Agonist-Induced Desensitization and Endocytosis of G-protein-Coupled Receptors 262
General Processes of GPCR Regulation 262
Mechanisms of GPCR Desensitization and Endocytosis 263
Functional Consequences of GPCR Endocytosis 265
References 266
Chapter 34: Functional Role(s) of Dimeric Complexes Formed from G-Protein-Coupled Receptors 270
Introduction 270
Historical Perspective 270
Heterodimerization Alters Receptor Function 272
Receptor Heterodimerization in Physiology and Pathology 274
Conclusion 276
Acknowledgements 276
References 276
Part 4: TGFß Receptors 280
Chapter 35: Receptor – Ligand Recognition in the TGFß Superfamily as Suggested by Crystal Structures of their Ectodomain Comple 282
Introduction 282
Ligand Structures 282
Receptor Structures 283
Receptor – Ligand Complexes 284
Concluding Remarks 287
Notes 287
References 288
Chapter 36: TGFß Signal Transduction 290
Introduction 290
TGFß Ligands 290
Receptors 291
Activation and Regulation of Receptors 292
The Smads: Effectors of TGFß Family Transcriptional Programs 293
Smad Activation 295
Regulation of TGFß Signal Transduction by Inhibitory Smads 295
Smads are DNA-Binding Proteins 296
Smads Cooperate with DNA-Binding Partners 296
Smads Interact with Transcription Co-Activators and Repressors 297
Non-Smad Signaling Pathways 297
References 298
Chapter 37: The Smads 302
History and Categorization: R-Smads, Co-Smads, and I-Smads 302
Smad Regulation by Receptors and Nucleocytoplasmic Shuttling 302
Transcriptional Regulation by Smads 302
Downregulation and Cross-Regulation of Smads 304
Function of Smads In Vivo: Gain of Function and Loss of Function Experiments 304
Acknowledgements 305
References 305
Part 5: TNF Receptors 308
Chapter 38: Structure and Function of Tumor Necrosis Factor (TNF) at the Cell Surface 310
Introduction 310
Structural Features 310
Signaling Pathways and Regulation 315
Biological Functions 315
Therapeutics and Future Expectations 316
Acknowledgement 317
References 317
Chapter 39: Tumor Necrosis Factor Receptor-Associated Factors in Immune Receptor Signal Transduction 322
Introduction 322
Discovery of TRAF Proteins 322
Biological Functions of TRAF Proteins 322
Domain Organizations and Structures of TRAFs 323
The Unique TRAF6 324
TRAF Signaling and LYS63 Linked Polyubiquitination 325
Regulation of TRAF Signaling 326
Summary and Perspectives 326
Acknowledgement 326
References 326
Part 6: Guanylyl Cyclases 330
Chapter 40: Guanylyl Cyclases 332
Historical Perspective 332
Overview of Mammalian Guanylyl Cyclases 332
Soluble Guanylyl Cyclase, Nitric Oxide, and Nitric Oxide Synthase 332
GC-A/NPR-A/NPR1 334
GC-B/NPR-B/NPR2 335
NPR-C/NPR-3 335
GC-C/STAR 335
GC-D 336
GC-E/RET-GC1 and GC-F/RET-GC2 336
GC-G 336
Acknowledgements 337
References 337
Section D: Other Transmembrane Signaling Proteins 342
Part 1: Adhesion Molecules 344
Chapter 41: Mechanistic Features of Cell-Surface Adhesion Receptors 346
Mechanosensory Mechanisms 346
Cell – Cell Adhesions/Adherens Junctions 347
T Cell Co-Stimulation 348
Axon Guidance and Neural Development 350
Conclusions 351
References 351
Chapter 42: Structural Basis of Integrin Signaling 354
Introduction 354
Structure 354
Quaternary Changes 355
Tertiary Changes 355
Tail Interactions 356
Concluding Remarks 356
References 356
Chapter 43: Carbohydrate Recognition and Signaling 358
Introduction 358
Biological Roles of Carbohydrate Recognition 358
Carbohydrate Structure and Diversity 358
Lectins and Carbohydrate Recognition 359
Carbohydrate-Mediated Signaling 359
Conclusions 362
References 362
Part 2: Ion Channels 366
Chapter 44: An Overview of Ion Channel Structure 368
Introduction 368
Obtaining Three-Dimensional Structures of Channels: Methods and Challenges 369
Prokaryotic Ion Channels: Gateways to Full Length Channel Structure 370
Open Channels 370
Eukaryotic Ion Channels at High Resolution: Whole Channels and Exploitation of Modular Structure to Divide and Conquer 371
Divide and Conquer: Exploitation of the Modular Nature of Ion Channel Structure 372
Ion Channel Complexes 373
References 373
Chapter 45: Voltage-Gated Calcium Channels 376
Physiological Roles of Voltage Gated Ca2+ Channels 376
Ca2+ Current Types Defined by Physiological and Pharmacological Properties 377
Molecular Properties of Ca2+ Channels 377
Ca2+ Channel Signaling Complexes 380
The Effector Checkpoint Model of Ca2+ Channel Regulation 383
References 383
Chapter 46: Store-Operated Calcium Channels 390
Store-Operated or Capacitative Calcium Entry 390
Store-Operated Channels – TRPs? 390
Major Players Identified: STIM and ORAI/CRACM 391
Signaling to Store-Operated Channels 391
References 392
Chapter 47: Intracellular Calcium Signaling 394
The “Calcium Signaling Toolkit” and Calcium Homeostasis 394
Channels Underlying Ca2+ Increase 395
Temporal Regulation of Ca2+ Signals 396
Spatial Regulation of Ca2+ Signals 397
References 398
Chapter 48: Cyclic Nucleotide-Regulated Cation Channels 400
Introduction 400
General Features of Cyclic Nucleotide-Regulated Cation Channels 400
CNG Channels 401
HCN Channels 402
Acknowledgement 403
References 403
Part 3: Immunoglobulin Receptors 406
Chapter 49: Immunoglobulin – Fc Receptor Interactions 408
Introduction 408
Immunoglobulin Structure 408
Fc Receptors and their Structures 409
IgG – Receptor Interactions 410
IgE – Receptor Interactions 411
IgA – Receptor Interactions 412
Conclusions 413
References 413
Chapter 50: T Cell Receptor/pMHC Complexes 416
TCR Generation and Architecture 416
Peptide Binding to MHC Class IA and II 417
TCR/pMHC Interaction 417
Orientation of the TCR in TCR/PMHC Complexes 417
Peptide Recognition by the TCR CDR Loops 418
Discrepancy Between Magnitude of Structural Changes and Biological Outcomes 419
Role of Bound Water in TCR/pMHC Recognition 420
Conclusions and Future Perspectives 420
References 421
Chapter 51: NK Receptors 424
Immunoreceptors 424
Natural Killer Cells 424
IG-Type NK Receptors: KIR 427
Other IG-Type Receptors on NK Cells 428
C-Type Lectin-Like NK Receptors: LY49A 428
C-Type Lectin-Like NK Receptors: NKG2D 429
References 429
Chapter 52: Toll-Like Receptors – Structure and Signaling 432
Structure of TLR3 432
The dsRNA Binding Site in hTLR3 432
TLR4 432
MD-2 434
TLR1 – TLR2 Dimerization by a Tri-Acylated Lipopeptide 435
Signaling 435
Acknowledgements 436
References 436
Chapter 53: Toll Family Receptors 438
Introduction 438
Structure – Function of Toll Receptors 438
Signaling by Toll Family Receptors 440
References 442
Index 444