Membrane Dynamics and Calcium Signaling (eBook)

Prof. Joachim Krebs is Prof. Emeritus of the Swiss federal Institute of Technology (ETH) ; at present he is Consultant at the MPI for Biophysical Chemistry, Department on NMR-based Structural Biology, Göttingen, Germany. Prof. Krebs was working for more than 30 years in the field of calcium signaling, calcium-binding and calcium-transport proteins and has importantly contributed to the understanding of calcium function and signaling pathways in the cell.

Preface 6
Contents 8
Part I: Plasma Membrane 10
Chapter 1: The Plasma Membrane Calcium Pump (PMCA): Regulation of Cytosolic Ca2+, Genetic Diversities and Its Role in Sub-plas... 11
1.1 Introduction 11
1.2 General Properties of PMCA 13
1.3 Structural Details of PMCA 15
1.4 Genetic Diversity of PMCA in Health and Disease 17
1.4.1 PMCA1 18
1.4.2 PMCA2 20
1.4.3 PMCA3 21
1.4.4 PMCA4 21
1.5 PMCA and Microdomains of Ca2+ Signaling 22
1.6 Conclusions 23
References 24
Chapter 2: Structure-Function Relationship of the Voltage-Gated Calcium Channel Cav1.1 Complex 30
2.1 Introduction 31
2.1.1 Classification of Voltage-Gated Calcium Channels 31
2.1.2 Molecular Properties of Cav 32
2.1.3 Channelopathies 33
2.2 Structural Studies of Voltage-Gated Calcium Channels 33
2.3 Structural Analysis of Cav1.1 35
2.3.1 The Overall Architecture of Cav1.1 35
2.3.2 Structure of the ?1 Subunit 35
2.3.3 The VSDs of Cav1.1 36
2.3.4 The Selectivity Filter 37
2.3.5 The Auxiliary Subunits 39
2.3.6 Structural Mapping of Disease-Associated Mutations 40
2.4 Voltage-Gated Calcium Channels in Excitation-Contraction Coupling 40
2.5 Perspective 43
References 43
Chapter 3: Structure-Dynamic Coupling Through Ca2+-Binding Regulatory Domains of Mammalian NCX Isoform/Splice Variants 47
3.1 Ca2+ Sensing by Isoform/Splice Variants and Multitask Ca2+ Signaling 48
3.2 Structural and Regulatory Specificities of NCX Isoform/Splice Variants 48
3.2.1 Coordination Chemistry Controls the Number and Affinity of Ca2+ Sites in Uniformly Folded CBDs 49
3.2.2 Each CBD Domain Plays a Distinct Regulatory Role 50
3.2.3 Exon Arrays Differentially Control the Tissue-Specific Regulatory Modes of NCX Variants 51
3.3 Synergistic Interactions Between CBDs Control the Ca2+ Sensing Features 53
3.3.1 CBD12 Crystal Structures Highlight the Functional Significance of the Two-Domain Interface 54
3.3.2 Ca2+ Dependent Rigidification Underlies Dynamic Coupling of CBDs 57
3.4 Structure-Dynamic Basis for Ca2+ Evoked Decoding of Regulatory Massage 57
3.5 Exon-Specific Roles in Editing the Regulatory Massage 58
3.6 Conclusions 60
References 61
Part II: Endoplasmic/Sarcoplasmic Reticulum 65
Chapter 4: The Endoplasmic Reticulum and the Cellular Reticular Network 66
4.1 Introduction 67
4.2 The ER 67
4.3 ER and Ca2+ Homeostasis 69
4.4 ER-Plasma Membrane Connection: Store-Operated Calcium Entry 69
4.5 ER and Protein Quality Control 71
4.6 ER and Cellular Stress Coping Response Strategies 71
4.7 ER and Lipid Metabolism 72
4.8 ER and Membrane Contact Sites 74
4.9 Conclusions 75
References 76
Chapter 5: Structure-Function Relationship of the SERCA Pump and Its Regulation by Phospholamban and Sarcolipin 82
5.1 Calcium Homeostasis 82
5.2 SERCA Isoforms and Human Disease (P-Type ATPases) 83
5.2.1 SERCA1 83
5.2.2 SERCA2 84
5.2.3 SERCA3 85
5.3 Catalytic Cycle of Calcium Transport by SERCA 86
5.4 Structural Studies of SERCA 88
5.4.1 Structural Insights into the SERCA Calcium Transport Cycle 90
5.5 Regulation of SERCA by Phospholamban 92
5.5.1 Introduction to Phospholamban 92
5.5.2 Oligomerization of Phospholamban and the Theory of Mass Action 94
5.5.3 SERCA Inhibition by Phospholamban 96
5.5.4 Structural Studies of Phospholamban and SERCA/Phospholamban Complex 98
5.5.5 Regulation of Phospholamban 100
5.5.6 Phospholamban in Heart Failure 102
5.5.6.1 Arg9-Cys (R9C) 102
5.5.6.2 Arg14-Deletion (R14del) 104
5.5.6.3 Arg9-Leu (R9L) and Arg9-His (R9H) 105
5.5.6.4 Leu39-Stop (L39stop) 106
5.5.6.5 Arg25-Cys (R25C) 106
5.5.6.6 Mutations in the Promoter and Intronic Regions 107
5.6 Regulation of SERCA by Sarcolipin 107
5.6.1 Introduction to Sarcolipin 107
5.6.2 Regulatory Mechanism of SERCA Inhibition by Sarcolipin 107
5.6.3 Structure of Sarcolipin 108
5.6.4 Oligomeric State of Sarcolipin 109
5.6.5 Sarcolipin Physically Interacts with SERCA 110
5.6.6 Role of Sarcolipin in the Heart 112
5.6.7 Sarcolipin Regulates Thermogenesis in Skeletal Muscle 114
5.7 Targeting SERCA Regulatory Complexes as Therapy for Cardiac Disease 114
5.8 Future Directions for SERCA Regulation 116
References 116
Chapter 6: Structural Insights into IP3R Function 125
6.1 Introduction 126
6.2 Historical Perspective on the Structural Studies of IP3R 127
6.3 Validation of the 3D Structure of IP3R 130
6.4 Near-Atomic Resolution Structure of Tetrameric IP3R Assembly 131
6.5 Structure-Function Conservation in Ca2+ Release Channel Family 140
6.6 Conclusions and Future Perspective 144
References 147
Chapter 7: IP3 Receptor Properties and Function at Membrane Contact Sites 152
7.1 The IP3 Receptor, the Main Ca2+-Release Channel of the Endoplasmic Reticulum 154
7.2 Mitochondrial and Lysosomal Ca2+ Handling in Cell Death and Survival Processes 157
7.2.1 Apoptosis and Its Regulation by Ca2+ 157
7.2.2 Autophagy and Its Regulation by Ca2+ 158
7.3 The Role of the IP3R at ER: Mitochondrial Contact Sites 159
7.3.1 IP3R-Mediated Ca2+ Signals in Cell Survival 161
7.3.2 IP3R-Mediated Ca2+ Signals in Apoptosis 164
7.4 The Role of the IP3R at ER: Lysosomal Contact Sites 165
7.5 Conclusions 167
References 168
Chapter 8: Structural Details of the Ryanodine Receptor Calcium Release Channel and Its Gating Mechanism 182
8.1 Introduction 182
8.2 Structure of RyR 186
8.3 Gating of RyR 193
8.4 Regulation of Gating 196
8.5 RyR in Diseases 198
8.6 Conclusions 201
References 201
Chapter 9: Store-Operated Calcium Entry: An Historical Overview 208
References 214
Chapter 10: From Stores to Sinks: Structural Mechanisms of Cytosolic Calcium Regulation 218
10.1 Calcium Signaling 219
10.2 N-Terminal Domain of IP3R 222
10.2.1 IP3-Induced Receptor Activation 224
10.2.2 Allosteric Regulation of Channel Gating by IP3 226
10.3 STIM1/2 EF-SAM Structure and Function 229
10.3.1 STIM1 Coiled-Coil Domain Structure and Function 232
10.3.2 Drosophila melanogaster Orai Crystal Structure and Function 234
10.3.3 STIM1 Coupling to Orai1 236
10.4 MCU Structure and Function 238
10.4.1 MCU N-Terminal Domain Structure and Function 240
10.5 Concluding Remarks 242
References 244
Chapter 11: Assembly of ER-PM Junctions: A Critical Determinant in the Regulation of SOCE and TRPC1 255
11.1 Introduction 256
11.2 The Molecular Components of SOCE 257
11.3 Regulation of TRPC1 Following ER-Ca2+ Depletion 261
11.4 Plasma Membrane Domains in Regulation of SOCE 263
11.5 PMCA, SERCA and Ca2+ Signaling Microdomains 266
11.6 The Role of Lipid Raft Domains in the Regulation of TRPC1 267
11.7 Conclusions 269
References 269
Part III: Mitochondria 279
Chapter 12: Beyond Intracellular Signaling: The Ins and Outs of Second Messengers Microdomains 280
12.1 Introduction 281
12.2 The Microdomain Concept 282
12.3 Ca2+ Microdomains 283
12.4 Ca2+ Microdomains at the ER-Mitochondria Interface: Generation and Functional Significance 288
12.5 Heterogeneity of Ca2+ Levels Within Organelles 292
12.5.1 ER/SR 292
12.5.2 Golgi Apparatus 295
12.5.3 Mitochondria 295
12.6 cAMP Microdomains 296
12.6.1 The Generation of cAMP Microdomains 297
12.6.2 cAMP Effectors 298
12.6.3 cAMP Generation 299
12.6.4 cAMP Degradation 300
12.6.5 Termination of cAMP Signaling 301
12.7 Ca2+ and cAMP Crosstalk 302
12.8 ATP Microdomains 305
12.9 Other Microdomains 309
12.10 Conclusions 309
References 310
Chapter 13: Mitochondrial VDAC, the Na+/Ca2+ Exchanger, and the Ca2+ Uniporter in Ca2+ Dynamics and Signaling 324
13.1 Overview 325
13.2 Mitochondria and Ca2+ Dynamics 325
13.3 Ca2+ Transporters in the Mitochondria 325
13.3.1 VDAC1: The Ca2+ Transporter in the OMM 326
13.3.1.1 VDAC1 Structure, Channel Conductance, Properties, and Regulation 326
13.3.1.2 VDAC1, a Multifunctional Channel Controlling Cell Metabolism 327
13.3.1.3 VDAC1 a Ca2+ Channel in the OMM 327
13.3.2 Ca2+ Transporters and Their Regulation in the IMM 329
13.3.2.1 MCU and Its Regulatory Proteins 329
13.3.2.2 Other Ca2+ Influx Pathways 330
13.3.3 Ca2+ Efflux Out of Mitochondria 330
13.3.3.1 NCLX Mediating Ca2+ Efflux 331
13.3.3.2 Other Proteins That have been Proposed to Mediate Ca2+ Efflux from Mitochondria 331
13.4 Mitochondria Ca2+, VDAC1 and Regulation of Metabolism 332
13.5 Mitochondrial Ca2+, VDAC1 and Regulation of Apoptosis 333
13.6 VDAC1 Function in ER/Mitochondria-Ca2+ Cross-Talk 334
13.7 microRNA Mediated Regulation of Mitochondrial Ca2+ Transporters and Channels 335
13.7.1 miRNAs Regulate VDAC1 335
13.7.2 miRNAs Regulate the MCU Complex 336
13.8 Defects of Other Mitochondrial Proteins in Ca2+ Homeostasis and Diseases 336
13.8.1 Diabetes 336
13.8.2 Cancer 336
13.8.3 Other Diseases 337
References 337
Part IV: Annexins 349
Chapter 14: Annexins: Ca2+ Effectors Determining Membrane Trafficking in the Late Endocytic Compartment 350
14.1 Introduction 351
14.2 Annexins: Ca2+ Binding and Ca2+ Sensitivity 352
14.2.1 Annexin A6: Location, Signalling and Dynamics 353
14.3 Intracellular Ca2+ Stores and Ca2+-Binding Proteins 355
14.3.1 Ca2+ in Acidic Compartments 358
14.3.2 Ca2+ and Annexins in the Endo- and Exocytic Pathways 360
14.4 Ca2+ Signalling and the Biogenesis, Function and Positioning of Acidic Compartments 362
14.4.1 Intra-Endosomal Trafficking: ILV Back-Fusion in MVBs 363
14.4.2 Lysosomal Exocytosis: A Selective Ca2+ Pathway 364
14.4.3 Ca2+ and Ca2+ Binding Proteins in Membrane Repair 366
14.4.3.1 Annexins: Masters in Membrane Repair 367
14.4.4 Ca2+ and Annexins Regulate Lysosomal Positioning 369
14.5 Concluding Remarks 370
References 371
Part V: Cytokinesis and Ca2+ Signaling 385
Chapter 15: Ca2+ Signalling and Membrane Dynamics During Cytokinesis in Animal Cells 386
15.1 Introduction 387
15.1.1 Historical Perspective 387
15.1.2 General Aspects of Cytokinesis 388
15.2 The Cytokinetic Ca2+ Transients 389
15.2.1 Generation of Distinct Ca2+ Transients During Cytokinesis 389
15.2.2 Identifying the Source of Ca2+ Generating Cytokinetic Transients 392
15.2.2.1 Positioning and Propagation Ca2+ Transients 393
15.2.2.2 Deepening and Apposition Ca2+ Transients 394
15.3 Possible Targets of the Cytokinetic Ca2+ Transients 395
15.3.1 The Positioning and Propagation Ca2+ Transients 395
15.3.2 The Deepening and Apposition Ca2+ Transients 399
15.4 Conclusions 403
References 404