The multi-authored book contains modern information on all major aspects related to the formation, stability and biological consequences of the asymmetrical organization of lipids in cell membranes. It introduces the phenomenon of membrane asymmetry, describes transmembrane distribution of lipids in biological membranes, represents methods for the measurement of the transmembrane lipid motion, emphasizes the role of flippases, discusses biological functions associated with lipid asymmetry and outlines correlations between lipid asymmetry and human diseases such as thrombosis, cancer, and apoptosis.Many different techniques that are used to measure the rate of transmembrane movement of lipids in biological systems and in model systems will be described in the book (see Table of contents, Part I and II: Use of Electron Spin Resonance with spin-labeled lipids or fluorescent lipids; analysis of vesicle or cell shape changes to determine lipid flip-flop rates). Relevance and use of probed lipids will be discussed extensively with many examples. Examples of flippase activity will be described in whole cells and also in reconstituted systems wherever possible. The molecular biology implied in the expression of the candidate flippases and the purification steps will be included although they are generally classical techniques.

Philippe F. Devaux, PhD, is Professor of Physics at the Paris 7 University. He has long-standing expertise in teaching molecular and cellular biophysics and physics applied to biology and medicine. He is the author of almost two hundred scientific papers and three books, and is an Editor of the European Biophysics Journal. Andreas Herrmann, PhD, is Professor of Molecular Biophysics at Humboldt-University of Berlin. He teaches courses on the subjects of molecular; cell; and membrane biophysics, optical spectroscopy, and fluorescence microscopy. He is the author of more than two hundred scientific papers focusing on lipid dynamics in biological membranes and molecular mechanisms of virus infection.

Introduction	p. xiii
List of Contributors	p. xxiii
Assessing Transmembrane Movement and Asymmetry of Lipids	p. 1
Methods for the Determination of Lipid Transmembrane Distribution and Movement in Biological Membranes	p. 3
Introduction	p. 3
Development of Assays for Distribution and Translocation of Lipids across Membranes	p. 4
Overview on Assays for Measuring Distribution and Translocation of Lipids across Cellular Membranes	p. 7
Main Techniques Used to Determine Transbilayer Distribution of Endogenous Lipids in Cell Membranes	p. 9
Main Techniques Used to Determine Transbilayer Distribution of Lipid Analogs in Cell Membranes	p. 12
Abbreviations	p. 21
References	p. 21
Detection and Measurement of Unlabeled Lipid Transmembrane Movement	p. 25
Introduction	p. 25
Measurement of Transmembrane Flip-Flop of Unlabeled Lipids by Shape Change of GUVs	p. 27
Measurement of Transmembrane Flip-Flop of Unlabeled Lipids Using AFM	p. 36
Conclusions	p. 41
Acknowledgments	p. 41
Abbreviations	p. 41
References	p. 42
Lipid Asymmetry in Cell Membranes	p. 45
New Insights in Membrane Lipid Asymmetry in Animal and Plant Cells	p. 47
Lipid Asymmetry in Animal Membranes	p. 47
Creating, Maintaining, or Randomizing the Membrane Phospholipid Distribution: Phospholipid Transporters	p. 49
What about Lipid Asymmetry and Translocation in Plant Cell Membranes?	p. 50
Abbreviations	p. 61
References	p. 61
Sphingolipid Asymmetry and Transmembrane Translocation in Mammalian Cells	p. 65
Introduction	p. 65
Sphingosine, Sphingosine-1-Phosphate, and Ceramide	p. 67
Ceramide	p. 68
Glycosphingolipids	p. 68
Sphingomyelin	p. 70
Future Perspectives	p. 71
Abbreviations	p. 71
References	p. 71
Transbilayer Movement and Distribution of Cholesterol	p. 75
Introduction	p. 75
Physicochemical Features of Cholesterol	p. 76
Methods for Measuring Cholesterol Transbilayer Movement and Distribution	p. 77
Transbilayer Movement of Cholesterol in Model Membranes	p. 81
Transbilayer Movement of Cholesterol in Biological Membranes	p. 82
Transbilayer Distribution of Cholesterol in Lipid and Biological Membranes	p. 82
Cholesterol Flip-Flop: Fast or Slow?	p. 87
Role of Proteins in the Transport of Cholesterol across Membranes	p. 88
Concluding Remarks	p. 90
Acknowledgment	p. 92
Abbreviations	p. 92
References	p. 93
Energy-Independent Protein-Mediated Transmembrane Movement of Lipids	p. 97
Phospholipid Flip-Flop in Biogenic Membranes	p. 99
Introduction	p. 99
Assays for Measuring Transbilayer Distribution of Endogenous Phospholipids	p. 100
Assays for Measuring Transbilayer Distribution and Movement of Phospholipid Analogs	p. 102
Shape Changes of GUVs as a Tool to Measure Flip-Flop	p. 106
Transbilayer Movement of Phospholipids in the ER	p. 108
Transbilayer Movement of Phospholipids in the Bacterial Inner Membrane	p. 110
Mechanism of Rapid Lipid Flip-Flop in Biogenic Membranes	p. 112
Efforts to Identify Phospholipid Flippases	p. 113
Flipping of Isoprenoid-Based Glycolipids	p. 115
Conclusion	p. 115
Abbreviations	p. 116
References	p. 116
Phospholipid Scramblase: When Phospholipid Asymmetry Goes Away	p. 119
Introduction	p. 119
Historical Overview	p. 120
Physiological Importance of Lipid Scrambling	p. 122
Characteristics of the Phospholipid Scrambling Process	p. 124
Toward Identification: Proposed Candidate Proteins and Mechanisms	p. 132
Concluding Remarks	p. 139
Abbreviations	p. 139
References	p. 140
Energy-Dependent Lipid Transport Across Membranes	p. 147
Flip or Flop: Mechanism and (Patho) Physiology of P4-ATPase-Catalyzed Lipid Transport	p. 149
Introduction	p. 149
P4-ATPases are Prime Candidate Phospholipid Translocases	p. 152
Mechanism of P4-ATPase-Catalyzed Lipid Transport: Role of Accessory Subunits	p. 156
Role of P4-ATPases in Vesicle-Mediated Protein Transport	p. 161
P4-ATPase Dysfunction and Disease	p. 162
Future Challenges	p. 166
Acknowledgments	p. 166
Abbreviations	p. 166
References	p. 167
Coupling Drs2p to Phospholipid Translocation, Membrane Asymmetry, and Vesicle Budding	p. 171
Introduction	p. 171
P4-ATPases in Budding Yeast	p. 172
Evidence That Drs2p Is a Flippase	p. 175
Drs2p in Protein Transport and Vesicle Budding	p. 183
Concluding Remarks	p. 191
Abbreviations	p. 192
References	p. 193
Substrate Specificity of the Aminophospholipid Flippase	p. 199
Introduction	p. 199
Substrate Specificity of the PM Aminophospholipid Flippase	p. 200
Identification and Substrate Specificity of Candidate Aminophospholipid Flippases	p. 205
Is the Lipid Specificity of Candidate Aminophospholipid Flippases Unique?	p. 210
Lipid Specificity of Other PS-Binding Proteins	p. 213
Sequence Elements That Bind to PS	p. 215
Conclusions	p. 216
Acknowledgments	p. 217
Abbreviations	p. 218
References	p. 218
The Flippase Delusion?	p. 225
ATP-Binding Cassette (ABC) Transporters and Lipid Flip-Flop	p. 225
ABCA4 and Lipid Translocation: Explaining a Phenotype?	p. 228
MsbA and Lipid Translocation: A Key to Survival	p. 230
Drug and Lipid Movement by ABCB1: Is the Mechanism a Flip-Flop?	p. 237
ABCB4: The Forgotten and Likely Lipid Flippase?	p. 240
Conclusions and Perspectives	p. 244
Abbreviations	p. 244
References	p. 245
Relevance of Lipid Transmembrane Distribution for Membrane Properties and Processes	p. 251
Membrane Lipid Asymmetry and Permeability to Drugs: A Matter of Size	p. 253
Introduction	p. 253
The Origin of Lipinski's Second Rule from the Point of View of the Pharmaceutical Industry	p. 254
Solving Lipinski's Second Rule	p. 257
Lipinski's Second Law and Potential Application	p. 264
Conclusion	p. 270
Acknowledgment	p. 272
Abbreviations	p. 272
References	p. 273
Endocytosis and Lipid Asymmetry	p. 275
Introduction	p. 275
Bending a Membrane	p. 276
Shape Changes of GUVs Induced by Lipid Asymmetry	p. 278
How Endocytosis Is Linked to Lipid Asymmetry	p. 280
Role of P4-ATPases in the Formation of Endocytic Invaginations	p. 283
Concluding Remarks	p. 284
Acknowledgments	p. 285
Abbreviations	p. 285
References	p. 285
Apoptosis and Diseases: Consequences of Disruption to Lipid Transmembrane Asymmetry	p. 289
Membrane Lipid Asymmetry in Aging and Apoptosis	p. 291
Introduction	p. 291
Phospholipid Transporters	p. 292
Lipid Asymmetry in Erythrocytes	p. 294
Lipid Asymmetry during Apoptosis	p. 297
Ca2+ Homeostasis during Apoptosis	p. 298
Membrane Phospholipid Asymmetry: Static or Dynamic?	p. 299
Regulation of Lipid Asymmetry during Apoptosis	p. 300
Significance	p. 304
Concluding Remarks	p. 306
Abbreviations	p. 306
References	p. 307
Phosphatidylserine Exposure in Hemoglobinopathies	p. 315
Introduction	p. 315
RBC Phospholipid Organization	p. 316
The RBC Flippase	p. 319
PS Exposure in RBCs	p. 324
PS Exposure in Hemoglobinopathies	p. 328
Consequences of PS Exposure	p. 329
Phospholipid Transbilayer Movement in Hemoglobinopathies	p. 330
Conclusion	p. 332
Abbreviations	p. 333
References	p. 334
Scott Syndrome: More Than a Hereditary Defect of Plasma Membrane Remodeling	p. 341
Introduction	p. 341
Scott Syndrome Features and Phenotype	p. 342
Cell Biology of Scott Syndrome	p. 343
Candidate Proteins in the Transmembrane Redistribution of PS	p. 345
The Significance of Membrane Vesiculation and of Derived MPs	p. 346
What Can Be Learned from Scott Syndrome?	p. 347
Conclusion	p. 348
Abbreviations	p. 349
References	p. 350
ABCA1, Tangier Disease, and Lipid Flopping	p. 353
Historical Notes: Tangier Disease (TD) and ATP-Binding Cassette Transporter 1 (ABCA1)	p. 353
The ABCA1 Gene and the Regulation of Its Expression	p. 354
The ABCA1 Protein and Its Interactions	p. 356
ABCA1: Mutations and Clinical Signs	p. 358
Targeted Inactivation and Overexpression of ABCA1 in Animal Models	p. 360
Liver and Macrophage ABCA1: Lipid Efflux and HDL Formation	p. 362
ABCA1 and Membrane Function	p. 363
ABCA1: Lipid Flop and Lipid Efflux	p. 364
ABCA1 and the Lipid Microenvironment at the Membrane	p. 366
Conclusions	p. 368
Acknowledgments	p. 369
Abbreviations	p. 369
References	p. 371
Index	p. 379
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