Contents
Preface XXVII
1 Basics of Cell Signaling 1
1.1 Cell Signaling: Why, When, and Where? 1
1.2 Intercellular Signaling 3
1.2.1 Tools for Intercellular Signaling 3
1.2.2 Steps of Intercellular Signaling 5
1.2.2.1 Formation of a Signal in the Signal-Producing Cell as a
Result of an External Trigger 5
1.2.2.2 Transport of the Signal to the Target Cell 6
1.2.2.3 Registration of the Signal in the Target Cell 6
1.2.3 Regulation of Intercellular Signaling 7
1.3 Hormones in Intercellular Signaling 8
1.3.1 The Chemical Nature of Hormones 8
1.3.2 Hormone Analogs: Agonists and Antagonists 11
1.3.2.1 Antagonists 11
1.3.2.2 Agonists 12
1.3.3 Endocrine, Paracrine, and Autocrine Signaling 13
1.3.3.1 Endocrine Signaling 14
1.3.3.2 Paracrine Signaling 15
1.3.3.3 Autocrine Signaling 15
1.3.4 Direct Protein Modification by Signaling Molecules 15
1.4 Intracellular Signaling: Basics 15
1.4.1 Reception of External Signals 16
1.4.2 Activation and Deactivation of Signaling Proteins 16
1.4.3 Processing of Multiple Signals 18
1.4.4 Variability of Signaling Proteins 18
1.5 Molecular Tools for Intracellular Signaling 18
1.5.1 Receptors 19
1.5.1.1 Receptors Receive External Signals and Trigger Intracellular
Signaling 19
1.5.1.2 Membrane-Bound Receptors 20
1.5.1.3 Intracellular Receptors 21
1.5.1.4 The Interaction Between Hormone and Receptor 21
1.5.1.5 Regulation of Receptor Activity 22
1.5.2 Signaling Enzymes 23
1.5.3 Scaffolding Proteins 24
1.5.4 Diffusible Intracellular Messengers: Second Messengers 25
2 Structural Properties, Regulation and Posttranslational
Modification of Signaling Proteins 27
2.1 Modular Structure of Signaling Proteins 27
2.1.1.1 Catalytic Domains 28
2.1.1.2 Targeting and Interaction Domains 28
2.1.1.3 Regulatory Domains 28
2.1.1.4 Unstructured, Flexible Sections 30
2.1.1.5 Multivalency 30
2.1.1.6 Differential Use of Modules 31
2.1.1.7 Multiple Inputs, Regulatory Influences, and Outputs 31
2.1.1.8 Subtypes of Signaling Modules 31
2.2 Modular Signaling Complexes 31
2.2.1.1 Specificity 33
2.2.1.2 Signal-Directed Assembly 33
2.2.1.3 Variability 33
2.2.1.4 Regulation 33
2.3 Regulation of Signaling Enzymes by Effector Binding 34
2.3.1.1 Allostery in Signaling Enzymes 34
2.3.1.2 Low-Molecular-Weight Effectors 35
2.3.1.3 Inhibitor Proteins 35
2.3.1.4 Activator Proteins 36
2.3.1.5 Metal Ions 36
2.4 Posttranslational Modifications (PTMs) in Cellular Signaling 36
2.4.1 Chemical Nature of PTMs 37
2.4.1.1 Allosteric and Conformational Functions of PTMs 38
2.4.1.2 Recognition of PTMs by Interaction Domains 38
2.4.1.3 Dynamic Nature of PTMs 38
2.4.1.4 Examples of Regulatory PTMs 38
2.4.2 Recognition of Protein Modifications by Modification-Specific
Interaction Domains 41
2.4.3 Multisite Protein Modification 42
2.4.3.1 PTM Patterns are Used as a “Bar Code” 43
2.4.3.2 Multiple Modifications Often Show Combinatorial Characteristics 43
2.4.4 Binding Properties of Regulatory Interaction Domains 43
2.4.4.1 Versatility and Variability of Interaction Domains 46
2.4.5 How Interaction Domains Read PTM Patterns 47
2.4.5.1 Inducible Interactions 47
2.4.5.2 Cooperative Interactions and Multisite PTMs 47
2.4.5.3 Sequential PTM-Dependent Interactions and
Cross-Regulation 47
2.4.5.4 Mutually Exclusive PTMs and Interactions 48
2.4.5.5 Antagonistic Action of PTMs 49
2.4.5.6 Regulation of Intramolecular Interactions by PTMs 49
2.4.5.7 Convergent Recognition of a PTM 50
2.5 Regulation by Protein Phosphorylation 51
2.5.1 General Aspects of Protein Phosphorylation 51
2.5.1.1 Properties and Interactions of Phosphorylated Proteins 52
2.5.2 Allosteric Functions of Protein Phosphorylation 53
2.5.3 Organization of Signaling Pathways by Protein Phosphorylation 54
2.5.3.1 Tyr-Phosphorylation 54
2.5.3.2 Ser/Thr Phosphorylation 54
2.6 Regulation by Protein Lysine Acetylation 55
2.6.1 General Aspects of Protein Lysine Acetylation 55
2.6.2 Enzymes of Protein Lysine Acetylation 56
2.6.2.1 HATs 56
2.6.2.2 HDACs 56
2.6.2.3 Cleavage Mechanism 57
2.6.3 Regulatory Functions of Lysine Acetylation 57
2.7 Regulation by Protein Methylation 58
2.7.1 Protein Lysine Methylation 58
2.7.1.1 Lysine Methyl Transferases 59
2.7.1.2 Lysine Demethylases, KDMs 59
2.7.1.3 Interaction Domains for Methylated Lysine 61
2.7.2 Protein Arginine Methylation 61
2.7.2.1 Arginine Demethylation/Citrullination 61
2.7.2.2 Interaction Domains 62
2.8 Ubiquitin Modification of Proteins 62
2.8.1 Pathways of Protein Degradation 63
2.8.1.1 Lysosomal Pathway 64
2.8.1.2 Autophagosomal Pathway 64
2.8.1.3 Proteasomal Pathway 64
2.8.2 Basics of Ubiquitin Modification 65
2.8.2.1 The Ub-Conjugation Reactions: E1, E2, and E3 Enzymes 66
2.8.2.2 E1: Activation of Ubiquitin 68
2.8.2.3 E2: Transacylation to the Ubiquitin-Conjugating Enzyme E2 68
2.8.2.4 E3: Ubiquitin Transfer to the Target 68
2.8.3 Structure and Regulation of Ub-Protein Ligases 69
2.8.3.1 Hect Domain E3 Enzymes 69
2.8.3.2 RING Domain E3 Enzymes 71
2.8.3.3 Structure and Regulation of Cullin-RING Ligases 73
2.8.3.4 Substrate Recognition by Cullin-RING Ligases 74
2.8.3.5 N-End Rule 74
2.8.3.6 Examples of Cullin-RINGE3 Ligases 75
2.8.3.7 SCF Complex 75
2.8.3.8 Anaphase-Promoting Complex (APC) 76
2.8.3.9 Cbl Proteins 77
2.8.4 Degradation in the Proteasome 78
2.8.4.1 The 20S Proteasome 78
2.8.4.2 The 19S Activator 80
2.8.5 Nonproteolytic Functions of Ubiquitin Conjugation 81
2.8.5.1 Deubiquitination 81
2.8.5.2 Multiplicity of Ub Conjugation 81
2.8.5.3 Ub-Binding Domains and Ub Receptors 84
2.8.5.4 Ub-Conjugation in Regulation of the NFkB Pathway 85
2.8.6 Ubiquitin-Like Proteins: Sumo-Modification 88
2.9 Lipidation of Signaling Proteins 90
2.9.1 Myristoylation 91
2.9.2 Palmitoylation 92
2.9.2.1 Functions of Palmitoylation 93
2.9.3 Farnesylation and Geranylation 93
2.9.4 Dual Lipidation 95
2.9.5 Cholesterol Membrane Anchor 95
2.9.6 The Switch Function of Lipid Anchors 96
2.9.7 The Glycosyl-Phosphatidyl-Inositol (GPI) Anchor 98
Questions 99
References 100
3 Organization of Signaling 103
3.1 Scaffold Proteins 103
3.1.1 General Aspects of Scaffold Proteins 103
3.1.2 Scaffolds as Organizers of Signaling Circuits 105
3.1.2.1 Organization of Sequential Signaling and Signaling
Circuits 106
3.1.2.2 Scaffolds Organize Signaling Complexes and are Targets of
Regulation 107
3.1.2.3 Scaffolds Organize Feedback Loops 107
3.1.2.4 Scaffolds as Signaling Enzymes and Allosteric Regulators 108
3.2 Signal Processing in Signaling Paths and Signaling Networks 108
3.2.1 Specificity of Signaling 109
3.2.2 PTM-Induced Formation of Signaling Complexes 109
3.2.3 Signaling through Preassembled Multiprotein Complexes 110
3.2.4 Signaling in Dependence of Subcellular Localization: Spatial
Organization 111
3.2.4.1 Spatial Control by Scaffolding 111
3.2.4.2 Spatial Control by Phosphorylation 112
3.2.4.3 Lipid Anchors 112
3.2.4.4 Clustering of Signaling Proteins on the Nanoscale 112
3.2.5 Temporal Control of Signaling 113
3.3 Architecture of Signaling Pathways 113
3.3.1 Linearity, Branching, Crosstalk, and Networks 114
3.3.1.1 Linearity 114
3.3.1.2 Branching 114
3.3.1.3 Crosstalk 114
3.3.1.4 Networks 115
3.3.2 Regulatory Circuits and Responses in Biological Networks 116
3.3.2.1 Circuits and Cascades 116
3.3.2.2 Feedback Loops 117
3.3.2.3 Negative Feedback 117
3.3.2.4 Positive Feedback 119
3.3.2.5 Bistability 120
3.3.2.6 Dynamic Behavior of Responses 121
3.3.3 Network Structures 121
3.3.3.1 Interaction Networks: Hubs 122
3.3.3.2 Layered Networks 124
3.3.3.3 Modularity 126
3.3.3.4 Redundancy and Robustness 126
Questions 127
References 127
4 The Regulation of Gene Expression 129
4.1 The Basic Steps of Gene Expression 129
4.1.1 Regulation of Transcription 129
4.1.1.1 Conversion of the pre-mRNA into the Mature mRNA 131
4.1.1.2 Regulation at the Level of mRNA and Translation 131
4.1.1.3 Nature of the Regulatory Signals 131
4.2 The Components of the Eukaryotic Transcription Machinery 131
4.2.1 The Basic Features of Eukaryotic Transcription 132
4.2.2 Elementary Steps of Eukaryotic Transcription 135
4.2.3 The Eukaryotic RNA Polymerases 135
4.2.4 The Core Promoter and Structure of the Transcription
Start Site 137
4.2.5 General Transcription Factors and the Basal Transcription
Apparatus 139
4.2.5.1 TFII D 139
4.2.5.2 TFIIH 141
4.2.6 The Mediator Complex 143
4.2.7 C-Terminal Domain (CTD) of RNA Polymerase II and
the Onset of Transcription 146
4.3 The Principles of Transcription Regulation 149
4.3.1 Elements of Transcription Regulation 149
4.3.2 Regulation of Eukaryotic Transcription by Specific Transcription
Factors 151
4.3.2.1 Activation and Repression of Transcription 152
4.3.3 Coregulators of Transcription 153
4.3.4 DNA-Binding of Specific Transcription Factors 153
4.3.4.1 DNA-Binding Domains 154
4.3.5 Structure of the Recognition Sequence and Quaternary Structure of
DNA-Binding Proteins 155
4.3.5.1 Palindromic Arrangement 155
4.3.5.2 Direct Repeats of the Recognition Sequence 155
4.3.5.3 Identity of a RE 156
4.3.5.4 Homodimers and Heterodimers 156
4.3.6 Communication with the Transcription Apparatus: Transactivation
Domains 157
4.3.7 Clustering of REs and the Enhanceosome 159
4.3.8 DNA Recognition and Selectivity of Transcription Activation 161
4.3.8.1 Sequence of the RE 161
4.3.8.2 Allostery in Transcription Factor–RE Interactions 162
4.3.8.3 Influence of Neighboring Sequences and Chromatin
Surrounding 162
4.3.9 Repression of Transcription 163
4.4 The Control of Transcription Factors 165
4.4.1 Classification of Transcription Factors by their Function in Signal
Transduction Networks 165
4.4.1.1 Constitutively Active Transcription Factors 166
4.4.1.2 Regulatory Transcription Factors 166
4.4.2 Mechanisms for the Control of the Activity of DNA-Binding
Proteins 167
4.4.2.1 Changes in the Concentration of Regulatory DNA-Binding
Proteins 169
4.4.2.2 Regulation by Binding of Effector Molecules 169
4.4.3 PTM of Transcription Regulators 170
4.4.3.1 Regulation by Phosphorylation 171
4.4.3.2 Regulation by Acetylation 175
4.5 Chromatin Structure and Transcription Regulation 175
4.5.1 Chromatin Architecture at Promoters 177
4.5.1.1 Histone Variants 180
4.5.1.2 Chromatin Remodeling 180
4.5.1.3 Chromatin Modification 182
4.5.2 Histone Acetylation 182
4.5.2.1 Histone Acetyltransferases 184
4.5.2.2 Histone Deacetylation 185
4.5.3 Histone Methylation 186
4.5.3.1 Enzymes of Histone Lysine Methylation 188
4.5.3.2 Enzymes of Histone Lysine Demethylation 189
4.5.3.3 Histone Arginine Methylation 189
4.5.4 Histone Phosphorylation 190
4.5.5 Histone Ubiquitination 192
4.5.6 Recognition of Histone Modifications by Protein Domains 192
4.5.7 Histone Modification Crosstalk 193
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