Modular protein domains /

Preface 7
Contents 9
List of Contributors 19
Prologue: An Overview of Protein Modular Domains as Adaptors 25
1 The SH2 Domain: a Prototype for Protein Interaction Modules 29
1.1 The Multidomain Nature of Signaling Proteins and Identification of the SH2 Domain 29
1.2 SH2 Domains as a Prototype for Interaction Domains 33
1.3 Structure and Binding Properties of SH2 Domains 33
1.4 Different Modes of SH2 Domain\u2013Phosphopeptide Recognition 36
1.5 Signaling Pathways and Networks 38
1.6 Plasticity of SH2 Domains 41
1.7 SH2 Domain Dimerization 43
1.8 Tandem SH2 Domains 44
1.9 Composite and Complex Interaction Domains 45
1.10 Allosteric Regulation 45
1.11 SH2 Domains and Disease 48
1.12 Summary 50
References 51
2 SH3 Domains 61
2.1 Brief Overview 61
2.2 Historical Perspective 63
2.2.1 Genetics to the Rescue 64
2.2.2 Structure and Specificity 65
2.3 Predicting Binding Partners 68
2.3.1 Core Peptide Docking vs. Extended Interactions 70
2.3.2 Atypical SH3 Docking Motifs 73
2.4 Experimental Exploitation of SH3 Specificity 76
2.5 Conclusion 78
References 79
3 The WW Domain 83
3.1 Introduction and Brief History of Module Discovery 83
3.2 Structure of the WW Domain\u2013Ligand Complex 84
3.3 WW Domains and Human Diseases 86
3.3.1 From Liddle\u2019s Syndrome to Liddle\u2019s Disease 86
3.3.2 Amyloid Precursor Protein: APP and FE65 87
3.3.3 Dystrophin WW Domain and Muscular Dystrophy 88
3.4 Emerging Directions and Recent Developments 89
3.4.1 AxCell\u2019s Map 89
3.4.2 ErbB4 Receptor Protein\u2013Tyrosine Kinase and its WW Domain-containing Adaptor, YAP 89
3.4.3 Membrane Proteins with PPxYs Implicated in Cancer 91
3.5 Concluding Remarks 91
References 93
4 EVH1/WH1 Domains 97
4.1 Introduction 97
4.2 Occurrence and Distribution of EVH1 Domains 98
4.2.1 Proteins Containing EVH1 Domains 101
4.2.2 Modular Architecture of EVH1-containing Proteins: Domain Location, Domain Combinations, and Copy Number 104
4.2.3 Classification of EVH1 Domains 106
4.3 Structures of EVH1 Domains and Their Complexes 107
4.3.1 High-resolution Structures of EVH1 and Related Domains 107
4.3.2 Structures of EVH1 Complexes and Determinants of Ligand Specificity 110
4.3.3 Comparisons with RanBDs, PTB Domains, and PH Domains 114
4.4 Biological Function and Signaling Pathways Involving EVH1 Domains 115
4.4.1 Ena/VASP Interactions 115
4.4.2 Homer/Vesl Interactions 116
4.4.3 WASP/N-WASP Interactions 116
4.4.4 Spred Interactions 117
4.5 Emerging Research Directions and Recent Developments 118
4.5.1 Use of Sequence and Structural Data in Prediction of Binding Partners 118
4.5.2 Use of Structural Data from Complexes to Guide the Rational Design of New Ligands 118
4.6 Concluding Remarks 119
References 120
5 The GYF Domain 127
5.1 Introduction 127
5.2 Structure of the CD2BP2-GYF Domain and Its Interaction with the CD2 Signaling Peptide SHRPPPPGHRV 129
5.3 Molecular and Signaling Function of GYF Domains 131
5.3.1 Sequence Specificity of the CD2BP2 GYF Domain 131
5.3.2 Spliceosomal Proteins Contain Binding Motifs for CD2BP2-GYF 132
5.3.3 Phage Display of CD2BP2-GYF 132
5.3.4 Sequence Repetition in GYF Domain-mediated Interactions 133
5.3.5 Functional Relevance of the CD2BP2-GYF Domain Interaction with CD2 134
5.3.5.1 Competitive Binding of CD2BP2-GYF and Fyn-SH3 to the CD2 Tail in Vitro 134
5.3.5.2 In Vivo Compartmentalization of CD2 Binding Proteins 135
5.3.6 Other GYF Domain\u2013Containing Proteins 135
5.4 Emerging Research Directions and Recent Developments 137
5.5 Concluding Remarks 138
References 139
6 PTB Domains 141
6.1 Introduction 141
6.2 Function of PTB Domain Proteins 142
6.2.1 Role of PTB Domain Proteins in Tyrosine Kinase Signaling 143
6.2.1.1 Shc 143
6.2.1.2 Proteins with PTBI Domains 143
6.2.1.3 Additional PTB Domain Proteins Involved in Tyrosine Kinase Signaling 145
6.2.2 PTB Domain Proteins That Function Independent of Phosphotyrosine 146
6.2.2.1 PTB Domain Proteins That Bind APP 146
6.2.2.2 PTB Domain Proteins That Bind Integrins 148
6.2.2.3 PTB Domain Proteins That Control Endocytosis 149
6.3 PTB Domain Structure 151
6.3.1 Broad Binding Specificity 153
6.3.2 Diverse Modes of Engagement 154
6.3.3 Phospholipid Binding 156
6.4 Conclusions 156
References 157
7 The FHA Domain 167
7.1 Introduction 167
7.2 FHA Domain Structure 171
7.2.1 Topology 171
7.2.2 FHA\u2013Phosphopeptide Interaction 173
7.2.3 A Second Binding Interface? 174
7.2.4 The FHA Domain is Part of a Domain Superfamily 175
7.3 Molecular and Signaling Function 176
7.3.1 FHA Domain Can Regulate Protein Localization 176
7.3.2 FHA Domain Binding to Enzyme Substrates 176
7.3.3 FHA Domain Binding to Regulators 177
7.3.4 Reversible Protein\u2013Protein Interactions 177
7.3.5 FHA Domain as a Transcriptional Activator Domain 178
7.4 Emerging Research Direction 179
7.4.1 Bacterial FHA Domains 179
7.4.2 A Potential Role for FHA Domains During Innate Immunity? 180
7.4.3 FHA Domain and Phosphothreonine-Proline Motifs 180
7.4.4 FHA Domain Chimeras as Phosphorylation Biosensors 181
7.5 Concluding Remarks 182
References 183
8 Phosphoserine/Threonine Binding Domains 187
8.1 Introduction 187
8.2 The 14-3-3 Proteins 188
8.2.1 History and Functions 188
8.2.2 Structure and Binding 190
8.3 WW Domains 191
8.4 FHA Domains 192
8.5 WD40 Repeats of F-box Proteins 194
8.6 Polo-box Domains 196
8.7 Conclusions and Future Directions 198
References 199
9 The Eukaryotic Protein Kinase Domain 205
9.1 Introduction 205
9.2 Architecture of the Kinase Domain 205
9.2.1 ATP Binding Pocket 207
9.2.2 Peptide Binding and Catalytic Residues 208
9.3 Catalytic Switching Mechanisms 209
9.3.1 Kinase Regulation by the A Loop 209
9.3.2 Regulation of Catalysis by Elements External to the Kinase Domain 211
9.3.2.1 Pseudosubstrate Regulation 212
9.3.2.2 Receptor Tyrosine Kinase Regulation by the Juxtamembrane Region 214
9.3.2.3 Intramolecular Regulation Involving Autonomously Folded Domains 215
9.4 Protein Kinase Substrate Recognition 217
9.4.1 Canonical Peptide Substrate Recognition 217
9.4.2 \u2018Phospho-priming\u2019\u2013Dependent Substrate Recognition 219
9.4.3 Regulation of AGC Kinases by the Hydrophobic Motif 220
9.4.4 CDK\u2013Cyclin Interactions with Substrates Mediated through the CY Motif 222
9.4.5 MAPK Docking Site Interactions: Common Recognition Mechanisms for Substrates, Activators, and Scaffolds 222
9.4.6 Substrate Recognition through a Phosphorylated Epitope in TGF尾 223
9.4.7 Substrate Recognition by the eIF2伪 Protein Kinases: Recognition of a Complex Epitope Presented by Globular Fold 224
9.5 Conclusions 225
References 225
10 Structure, Specificity, and Mechanism of Protein Lysine Methylation by SET Domain Enzymes 235
10.1 Discovery and Biology of SET Domains 235
10.2 Structure of the SET Domain 236
10.2.1 The SET Domain Fold 237
10.2.2 The Active Site 238
10.2.3 Interactions with Other Domains 239
10.3 Substrate Specificity and Catalytic Mechanism 241
10.3.1 Substrate Specificity 241
10.3.2 Catalytic Mechanism 243
10.3.3 Methylation Multiplicity 245
10.4 Emerging Directions and Conclusions 245
References 246
11 The Structure and Function of the Bromodomain 251
11.1 Introduction 251
11.2 The Bromodomain Structure 253
11.3 The Bromodomain as an Acetyl-lysine Binding Domain 254
11.3.1 Acetyl-lysine Binding 254
11.3.2 Molecular Determinants of Ligand Specificity 256
11.4 Emerging Developments 258
11.5 Concluding Remarks 259
References 260
12 Chromo and Chromo Shadow Domains 265
12.1 Introduction and Brief History of the Module\u2019s Discovery 265
12.2 Structures of the Chromo and Chromo Shadow Domains 266
12.3 Function of the Chromo Domain 270
12.4 Genetic, Cytological, and Molecular Properties of the Chromo Domain 272
12.5 Emerging Research Directions and Recent Developments 274
References 275
13 PDZ Domains: Intracellular Mediators of Carboxy-terminal Protein Recognition and Scaffolding 281
13.1 Introduction 281
13.2 Structural Analysis of PDZ Domains 283
13.3 Analysis of PDZ Domain\u2013Ligand Interactions with Mutagenesis and Synthetic Peptides 285
13.4 Molecular and Signaling Functions of PDZ Domains 287
13.4.1 INAD as a Molecular Scaffold 287
13.4.2 LIN-7\u2013Receptor Tyrosine Kinase Interactions and Subcellular Localization 289
13.4.3 PDZ Domain Proteins and Epithelial Polarity Induction and Maintenance 291
13.4.4 A Few Miscellaneous Examples: The Synapse, Disheveled, CARD MAGUKs, and Beta Adrenergic Receptors 293
13.5 Concluding Remarks 296
References 297
14 EH Domains and Their Ligands 303
14.1 Introduction 303
14.2 EH Domain-containing Proteins 303
14.3 Peptide Ligands 306
14.4 Cellular Ligands 308
14.5 Structures of the Domain and Its Ligands 309
14.6 Evolutionary Origins of the EH Domain 310
14.7 Functions of the EH Domain 312
References 313
15 Ubiquitin Binding Modules: The Ubiquitin Network Beyond the Proteasome 315
15.1 Introduction: The Ubiquitin System in Proteolysis and Beyond 315
15.2 CUE and UBA Domains 317
15.3 The Ubiquitin-interacting Motif 323
15.4 The UEV Domain 326
15.5 The PAZ and NZF Domains 329
15.6 Ubiquitin-based Networks 332
15.7 Conclusions 336
References 337
16 The Calponin Homology (CH) Domain 345
16.1 Introduction and Brief History 345
16.2 Structure of the Domain \u2013 The CH Domain Fold 347
16.2.1 Structures of Single CH Domains 349
16.2.2 Structures of Tandem CH Domains 349
16.3 Molecular and Signaling Function 350
16.3.1 Actin-binding Domains 350
16.3.2 Single EB-type CH Domains Function as Microtubule Anchors 351
16.3.3 Kinases, Phospholipids, and Other Cytoskeletal Components 352
16.3.4 CH Domain-containing Proteins and Human Diseases 354
16.3.4.1 The Dystrophin ABD and Muscular Dystrophy 354
16.3.4.2 The Filamin ABD and Otopalatodigital Syndromes 354
16.3.4.3 The 伪-Actinin ABD and Glomerulosclerosis 354
16.3.4.4 The 尾-Spectrin ABD and Spherocytosis 355
16.4 Emerging Research Directions and Recent Developments 355
16.5 Concluding Remarks 356
References 356
17 PH Domains 361
17.1 Introduction 361
17.2 PH Domain Structure and Phosphoinositide Binding 362
17.2.1 Overall Structure \u2013 The PH Domain Fold 362
17.2.2 Structural Basis for Phosphoinositide Binding 364
17.2.2.1 High-affinity PtdIns(4,5)P(2) Binding 364
17.2.2.2 Low-affinity PtdIns(4,5)P(2) Binding 364
17.2.2.3 Specific Recognition of Phosphoinositide 3-Kinase Products 365
17.2.2.4 PH Domains with Other Phosphoinositide-binding Specificities 369
17.2.2.5 Sequence Predictors of Phosphoinositide Binding 369
17.3 Molecular and Signaling Function of PH Domains 370
17.3.1 PH Domains as Phosphoinositide-dependent Membrane-targeting Domains 370
17.3.1.1 PtdIns(4,5)P(2)-specific PH Domains 371
17.3.1.2 PI 3-kinase Product-binding PH Domains 372
17.3.1.3 Membrane Targeting by PH Domains with Little Phosphoinositide-binding Specificity 373
17.3.2 Function of Low-affinity PH Domains That Are Not Independently Membrane Targeted 374
17.3.2.1 The Dynamin PH Domain 375
17.3.2.2 PH Domains of Dbl-family Proteins 375
17.3.3 Protein Targets of PH Domains 377
17.3.3.1 Small GTPases as PH Domain Targets 377
17.3.3.2 Other Protein Targets of PH Domain Targets 378
17.4 Emerging Research Directions and Recent Developments 380
References 381
18 ENTH and VHS Domains 389
18.1 Introduction 389
18.2 History of ENTH 390
18.3 Structure of ENTH Domains 393
18.4 Signaling and Molecular Functions of ENTH 395
18.5 History of VHS 398
18.6 Structure of VHS Domains 399
18.7 Function of GGA-VHS Domains 401
18.8 Function of Non-GGA VHS Domains 403
18.9 Involvement of ENTH and VHS Domains in Human Disease 404
18.10 Emerging Research Directions 404
18.11 Concluding Remarks 406
References 406
19 PX Domains 413
19.1 Introduction and History of the PX Domain Discovery 413
19.2 Structure of the PX Domain 416
19.2.1 Mechanism of PtdIns(3)P Coordination 418
19.3 Biological Function of the PX Domain 421
19.3.1 PI Binding Specificity 421
19.3.2 Synergistic Phospholipid Interactions 422
19.3.3 Membrane Insertion 422
19.3.4 Regulatory Protein Interactions 423
19.3.5 Signaling Pathways of the PX Proteins 424
19.4 Emerging Research Directions and Recent Developments 427
References 428
20 Peptide and Protein Repertoires for Global Analysis of Modules 433
20.1 Introduction 433
20.2 Repertoires from Cell Extracts 434
20.3 Repertoires of Proteins Based on Expression Cloning of DNA Libraries 434
20.3.1 Ligand Repertoires Used with the Yeast Two-Hybrid System 435
20.3.2 Module Repertoires Used with the Yeast Two-Hybrid System 436
20.3.3 Phage Expression Libraries of Ligands 437
20.3.4 Phage Expression Libraries of Modules 437
20.3.5 Phage Display of Protein Ligands 439
20.3.6 Phage Display of Protein Domains 439
20.3.7 Protein Arrays as Ligand Repertoires 440
20.3.8 Protein Arrays as Domain Repertoires 440
20.3.9 Mutagenized Domain Libraries 441
20.3.9.1 Site-directed Mutagenesis 441
20.3.9.2 Random Mutagenesis 442
20.4 Repertoires of Peptide Ligands Based on Expression Cloning of Oligonucleotide Libraries 443
20.4.1 Random Peptide Libraries 444
20.4.2 Dedicated Peptide Libraries 446
20.5 Synthetic Peptide Repertoires 448
20.5.1 Soluble Peptide Libraries as Ligand Repertoires 450
20.5.2 Bead-bound Peptide Libraries as Ligand Repertoires 450
20.5.3 Peptide Arrays as Ligand Repertoires 451
20.5.3.1 Sublibrary Pools for Iterative A Priori Deconvolution 451
20.5.3.2 Protein Scanning Repertoires (Peptide Walking) 452
20.5.3.3 Replacement Repertoires 452
20.5.3.4 Genome/Proteome Scanning 452
20.5.4 Peptide Arrays as Domain Repertoires 453
References 454
21 Computational Analysis of Modular Protein Architectures 463
21.1 Introduction 463
21.2 Protein Architecture: Sequence, Structure, and Function 463
21.2.1 The Modular Model of Protein Function 463
21.2.2 Partitioning of Protein Space 465
21.3 Analyzing Globular Domains 466
21.3.1 Globularity of Domains 467
21.3.2 Resources for Analysis of Globular Domains 468
21.3.3 SMART: Simple Modular Architecture Research Tool 468
21.3.3.1 The SMART Alignment Set 469
21.3.3.2 SMART Relational Database System 471
21.3.3.3 Web Interface 471
21.3.3.4 Application of SMART 474
21.3.4 Other Features and Resources 475
21.3.4.1 Globular Repeats 475
21.3.4.2 Domain Interaction Prediction 475
21.3.4.3 No Domains? 475
21.4 Analyzing Nonglobular Protein Segments 476
21.4.1 Unstructured Regions: Protein Disorder 477
21.4.1.1 What Role Does Protein Disorder Play in Biology? 478
21.4.1.2 What is Protein Disorder? 479
21.4.1.3 Methods for Finding Protein Disorder 481
21.4.1.4 GlobPlotting 481
21.4.1.5 Prediction of Multiple Types of Disorder with DisEMBL 483
21.4.1.6 Design of Protein Expression Vectors 486
21.4.2 Function Prediction for Nonglobular Protein Segments 486
21.4.2.1 Available Resources 487
21.4.3 The Eukaryotic Linear Motif Resource: ELM 487
21.4.3.1 ELM Annotation \u2013 \u2018Site seeing\u2019 489
21.4.3.2 ELM Resource Architecture 489
21.4.3.3 Knowledge-based Decision Support (KBDS): ELM Filtering 490
21.4.3.4 Using ELM 493
21.5 URLs 493
21.6 Concluding Remarks 495
References 496
22 Nomenclature for Protein Modules and Their Cognate Motifs 501
22.1 Introduction 501
22.2 Protein Modules 501
22.3 Functional Sites and Their Recognition Modules 503
22.4 Representation of Motifs and Functional Sites 504
22.5 Application of the Seefeld Convention to a Complex Example 507
22.6 New Directions 508
References 509
Epilogue: New Levels of Complexity in the Functional Roles of Modular Protein Interaction Domains: Switches and Sockets in the Circuit Diagrams of Cellular Systems Biology 511
Subject Index 517