1 INTRODUCTION 1
General features of membranes 1
Paradigm 1：the amphiphilic molecules in membranes assemble spontaneously due to the hydrophobic effect 4
Paradigm 2：the Fluid Mosaic Model describes the membrane structure 5
A shift in the paradigm：biomembranes have lateral domains that form “rafts” 9
A view for the future：dynamic protein complexes crowd the membrane interior and extend its borders 9
For further reading 13
2 THE DIVERSITY OF MEMBRANE LIPIDS 14
The acyl chains 14
Complex lipids 17
Phospholipids 19
Sphingolipids 20
Sterols and linear isoprenoids 21
The lipid bilayer matrix 22
Structure of bilayer lipids 22
Diffusion of bilayer lipids 24
Lipid asymmetry and membrane thickness 27
Lipid polymorphism 28
Lamellar phase 28
Hexagonal phase and the amphiphile shape hypothesis 29
Cubic phase 30
Miscibility of bilayer lipids 31
Lateral domains and lipid rafts 34
Detergent-resistant membranes 35
Diversity of lipids 37
Conclusion 39
For further reading 41
3 TOOLS FOR STUDYING MEMBRANE COMPONENTS：DETERGENTS AND MODEL SYSTEMS 42
Detergents 43
Types of detergents 43
Mechanism of detergent action 46
Membrane solubilization 49
Lipid removal 51
Model membranes 51
Monolayers 52
Planar bilayers 54
Patch clamps 57
Supported bilayers 57
Liposomes from SUVs to GUVs 60
Multilamellar vesicles 60
Small unilamellar vesicles 61
Large unilamellar vesicles 61
Short-chain/long-chain unilamellar vesicles 62
Giant unilamellar vesicles 62
Mixed micelles and bicelles 63
Blebs and blisters 64
Nanodiscs 66
Conclusion 67
For further reading 67
4 PROTEINS IN OR AT THE BILAYER 69
Classes of proteins that interact with the membrane 69
Proteins at the bilayer surface 70
Extrinsic/peripheral membrane proteins 70
Amphitropic proteins 74
Lipid-anchored proteins 74
Reversible interactions of peripheral proteins with the lipid bilayer 77
Effects of peripheral protein binding on membrane lipids 77
Interactions between peripheral proteins and lipids 78
Domains involved in binding the membrane 81
Curvature 83
Modulation of binding 84
Proteins and peptides that insert into the membrane 85
Toxins 86
Colicins 88
Peptides 88
SecA：protein acrobatics 90
Proteins embedded in the membrane 91
Monotopic proteins 91
Integral membrane proteins 91
Protein-lipid interactions 97
Hydrophobic mismatch 101
For further reading 103
5 BUNDLES AND BARRELS 105
Helical bundles 105
Bacteriorhodopsin 105
Photosynthetic reaction center 109
The proteins 110
Lipids 112
The cofactors 112
Antennae 113
The reaction cycle 114
β-barrels 115
Porins 117
OmpF and OmpC 118
VDAC，a mitochondrial porin 122
Specific porins 123
PhoE，the phosphoporin 123
LamB，the maltoporin 124
Other β-barrel transporters 124
Iron receptors 125
Outer membrane secretory proteins：not β-barrels 126
Conclusion 127
For further reading 127
6 FUNCTIONS AND FAMILIES 130
Membrane enzymes 130
Diacylglycerol kinase 132
Presenilin，an intra-membrane protease 134
P450 cytochromes 136
Transport proteins 137
Transport classifcation system 138
Superfamilies of ATPases 139
ABC transporter superfamily 140
Group translocation 140
Symporters 142
Antiporters 142
Ion channels 143
Membrane receptors 144
Nicotinic acetylcholine receptor 144
G protein-coupled receptors 145
Bioinformatics tools for membrane protein families 146
Predicting TM segments 146
Hydrophobicity plots 148
Orientation of membrane proteins 149
The positive-inside rule 150
Inverted repeats 151
Genomic analysis of membrane proteins 153
Helix-helix interactions 162
Proteomics of membrane proteins 163
Predicting β-barrels 164
For further reading 165
7 PROTEIN FOLDING AND BIOGENESIS 168
Protein folding 169
Folding α-helical membrane proteins 170
bR folding studies 173
Folding studies of β-barrel membrane proteins 175
Other folding studies 177
Whole protein hydrophobicity scale 178
Biogenesis of membrane proteins 178
Export from the cytoplasm 180
The translocon 187
The translocon structure 187
TM insertion 189
Biological hydrophobicity scale 191
Topogenesis in membrane proteins 195
Misfolding diseases 198
For further reading 201
8 DIFFRACTION AND SIMULATION 203
Back to the bilayer 203
Liquid crystallography 204
Liquid crystal theory 206
Joint refinement of x-ray and neutron diffraction data 207
Modeling the bilayer 209
Simulations of lipid bilayers 209
Molecular dynamics 209
Monte Carlo 213
Lipids observed in x-ray structures of membrane proteins 215
Crystallography of membrane proteins 219
A multidisciplinary approach 223
For further reading 225
9 MEMBRANE ENZYMES 226
Prostaglandin H2 synthase 227
OMPLA 230
Membrane proteases 234
Omptins 234
Intramembrane proteases 235
Rhomboid protease 236
Structure of the bacterial rhomboid GlpG 237
Formate dehydrogenase 239
P-type ATPases 243
Ca2+ ATPases 243
Na+，K+ ATPase 250
Other P-type ATPases 254
Conclusion 255
For further reading 255
10 MEMBRANE RECEPTORS 257
G protein-coupled receptors 258
Rhodopsin，a light-sensitive GPCR 259
Ground state rhodopsin 260
Activated rhodopsin 261
Rhodopsin as prototype 263
Adrenergic receptors 267
β2AR structure 268
β1AR structure 270
Activated β2AR in complex with Gs 270
Neurotransmitter receptors 274
Glutamate receptors：GluA2 274
Cys-loop receptors and GluCl 278
Conclusion 282
For further reading 282
11 TRANSPORTERS 284
Secondary transporters 284
MFS transporters 285
LacY，a scrutinized symporter 285
GlpT，an MFS antiporter 288
EmrD，an MFS exporter in an occluded conformation 289
FucP，an MFS symporter in co conformation 290
A paradigm for MFS transporters 291
Mitochondrial ADP/ATP carrier 291
AAC structure 291
Neurotransmitter transporters 294
Glutamate transporters and GltPh 294
Neurotransmitter sodium symporters and LeuT 296
LeuT structure 298
Transport mechanism of LeuT 300
The NSS family and the LeuT （APC-fold） superfamily 300
BetP and osmoregulated transport 303
ABC transporters and beyond 306
Maltose transporter 306
The vitamin B12 uptake system 310
BtuCD-BtuF，an ABC transport system 311
BtuB，an outer membrane transporter energized by TonB 313
Drug efflux systems 316
Sav1866 and P-glycoprotein，ABC exporters 316
EmrE，an example of dual topology 318
Tripartite drug efflux via a membrane vacuum cleaner 320
AcrB，a peristaltic pump 321
Alternating site mechanism of AcrB 322
AcrA，a periplasmic adaptor protein 323
TolC，the channel-tunnel 323
Partners of TolC 325
Conclusion 325
For further reading 326
12 CHANNELS 328
Aquaporins and glyceroaquaporins 329
Structure of aquaporins 330
Glyceroaquaporins：GlpF 331
Human aquaporins：AQP4 333
Potassium channels 335
KcsA structure and selectivity 336
Gating and activation 337
Voltage gating 339
Gating in human potassium channels 341
Chloride channels and the CLC family 343
ClC-ec1 344
CLC channels as “broken transporters” 346
Mechanosensitive ion channels 347
MscL 349
MscS 350
MS channel gating 351
Gap junction channels 354
Conclusion 356
For further reading 356
13 ELECTRON TRANSPORT AND ENERGY TRANSDUCTION 358
Complexes of the respiratory chain 359
Complex Ⅰ 359
Conformational coupling mechanism 363
Cytochrome bc1 365
The Q cycle 366
High-resolution structures 366
Cytochrome c oxidase 371
High-resolution structures 371
Oxygen reduction 373
Proton pathways 374
F1F0-ATP synthase 375
Subunit structure and function 377
F1 Domain 377
F0 Domain 379
Regulation of the F1F0-ATPase 379
Catalytic mechanism of a rotary motor 380
Rotational catalysis 380
Conclusions 383
For further reading 383
14 IN PURSUIT OF COMPLEXITY 385
Complex formation 386
Conformational changes and dynamics 390
For further reading 392
Appendix Ⅰ：Abbreviations 393
Appendix Ⅱ：Single-Letter Codes for Amino Acids 397
Index 399