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ABC TRANSPORTERS: AN INTRODUCTION AND OVERVIEW
PART I: PHYLOGENY AND EVOLUTION OF ABC TRANSPORTERS
Chapter 1: PHYLOGENETIC AND FUNCTIONAL CLASSIFICATION OF ABC (ATP-BINDING CASSETTE) SYSTEMS
INTRODUCTION
INVENTORY AND CLASSIFICATION OF ABC SYSTEMS
FAMILIES OF ABC SYSTEMS IN LIVING ORGANISMS
LESSONS FROM GENOME COMPARISONS
CONCLUSIONS AND PERSPECTIVES
Chapter 2: MEMBRANE TOPOLOGY OF THE HUMAN ABC TRANSPORTER PROTEINS
INTRODUCTION
METHODOLOGY
MEMBRANE TOPOLOGY OF THE ABC TRANSPORTERS
CONCLUSIONS
Chapter 3: HUMAN AND DROSOPHILA ABC PROTEINS
INTRODUCTION
PHYLOGENETIC ANALYSIS OF HUMAN ABC GENES
DROSOPHILA ABC GENES
HUMAN ABC GENE SUBFAMILIES
CONCLUSIONS AND PERSPECTIVES
PART II: FUNDAMENTAL ASPECTS OF THE MECHANISM OF ACTION OF ABC TRANSPORTERS
Chapter 4: STRUCTURE OF ABC TRANSPORTERS
INTRODUCTION
STRUCTURES OF NBDS
STRUCTURES OF INTACT ABC TRANSPORTERS
CONCLUSIONS
ACKNOWLEDGMENTS
Chapter 5: SUBSTRATE-BINDING SITES IN ABC TRANSPORTERS
GENERAL INTRODUCTION
PROPERTIES OF SUBSTRATES RECOGNIZED BY ABC TRANSPORTERS
LOCATION(S) AND NUMBER OF SUBSTRATE-BINDING SITES IN ABC TRANSPORTERS
STRUCTURAL AND FUNCTIONAL PROPERTIES OF SUBSTRATE-BINDING SITES
COUPLING BETWEEN SUBSTRATE-BINDING SITES AND NUCLEOTIDE-BINDING DOMAINS
THE TRANSPORT CYCLE OF ABC TRANSPORTERS
CONCLUDING REMARKS
ACKNOWLEDGMENTS
Chapter 6: PROBING OF CONFORMATIONAL CHANGES, CATALYTIC CYCLE AND ABC TRANSPORTER FUNCTION
INTRODUCTION
THE CATALYTIC CYCLE OF PGP AND OTHER ABC TRANSPORTERS – AN OVERVIEW
VACUUM CLEANER MODEL FOR ABC MULTIDRUG TRANSPORTERS
PROBING CONFORMATIONAL CHANGES OF PGP DURING THE CATALYTIC CYCLE
CONFORMATIONAL CHANGES IN OTHER ABC TRANSPORTERS
DOMAIN INTERACTIONS IN ABC TRANSPORTERS
Chapter 7: X-RAY STRUCTURE OF AN INTACT ABC TRANSPORTER, MSBA
INTRODUCTION: THE MULTIDRUG RESISTANCE (MDR) ABC TRANSPORTERS
STRUCTURAL STUDIES OF MDR-ABC TRANSPORTERS
PROTEIN EXPRESSION
PROTEIN PURIFICATION
PROTEIN CRYSTALLIZATION
CRYSTALLOGRAPHIC ANALYSIS
STRUCTURE DESCRIPTION
POSSIBLE FLIPPING MECHANISM
ACKNOWLEDGMENTS
PART III: PROKARYOTE ABC TRANSPORTERS
Chapter 8: INTRODUCTION TO BACTERIAL ABC PROTEINS
NATURE AND COMPOSITION OF THE ABC TRANSPORTER
AN ABUNDANCE OF DIFFERENT TYPES OF ABC PROTEINS IN PROKARYOTES
AN ADDITIONAL CLASS OF BACTERIAL ABCs INVOLVED IN DNA RECOMBINATION AND REPAIR
EXPORTERS
CLASS 2, ORPHAN ABCS
IMPORTERS
MEMBRANE DOMAINS OF THE BACTERIAL TRANSPORTERS ARE POORLY UNDERSTOOD
STRUCTURE AND FUNCTION OF THE ABC TRANSPORTERS
Chapter 9: IMPORT OF SOLUTES BY ABC TRANSPORTERS – THE MALTOSE AND OTHER SYSTEMS
INTRODUCTION AND GENERAL OVERVIEW
THE MALTOSE/MALTODEXTRIN TRANSPORT SYSTEM OF E. COLI AND S. TYPHIMURIUM
CURRENT TRANSPORT MODELS
CONCLUSIONS AND PERSPECTIVES
ACKNOWLEDGMENTS
Chapter 10: CRYSTAL STRUCTURES OF PERIPLASMIC SOLUTE-BINDING PROTEINS IN ABC TRANSPORT COMPLEXES ILLUMINATE THEIR FUNCTION
INTRODUCTION
STRUCTURE AND SUBSTRATE BINDING
LIGAND BINDING
INTERACTIONS OF PBPS WITH MEMBRANE COMPONENTS
EVOLUTION OF PERIPLASMIC BINDING PROTEINS
PROTEINS WITH RELATED FOLDS TO THE PBPS
PERSPECTIVES
ACKNOWLEDGMENT
Chapter 11: BACTERIAL ABC TRANSPORTERS INVOLVED IN PROTEIN TRANSLOCATION
INTRODUCTION
PHYLOGENY OR CLUSTER ANALYSIS OF THE ABC-ATPASE INVOLVED IN TYPE 1 SECRETION
GENETIC BASIS OF THE TYPE 1 SECRETION SYSTEM
PROMISCUITY OF THE ABC SECRETION SYSTEM
ALLOCRITES FOR TYPE 1 SECRETION SYSTEMS
TYPE 1 SECRETION OF LARGE POLYPEPTIDES INVOLVES A C-TERMINAL TARGETING SIGNAL
THE RTX SECRETION SIGNAL HAS A DUAL FUNCTION
SEVERAL ANTIBACTERIAL PEPTIDES SECRETED VIA THE TYPE 1 SYSTEM EMPLOY AN N-TERMINAL TARGETING SIGNAL
COMPOSITION OF THE TYPE 1 SECRETION TRANSLOCATOR
BOTH MFP AND ABC COMPONENTS OF THE TYPE 1 TRANSLOCATOR MAY BE INVOLVED IN RECOGNITION OF THE SECRETION SIGNAL OF THE TRANSPORT SUBSTRATE
GENERAL ORGANIZATION OF ABC TRANSPORTERS FOR TYPE 1 SECRETION: SOME HAVE A SPECIFIC PROTEASE DOMAIN
TOPOLOGY OF THE MEMBRANE DOMAIN OF HLYB
GENETIC ANALYSIS OF HLYB.
ATTEMPTS TO PURIFY THE INTACT ABC TRANSPORTER ASSOCIATED WITH TYPE 1 SECRETION
PROPERTIES OF THE PURIFIED ABC DOMAIN
THE FORM OF TYPE 1 PROTEINS DURING TRANSLOCATION: FOLDED OR UNFOLDED?
WHAT ROLE FOR HLYB IN THE TRANSLOCATION OF HLYA?
STRUCTURE OF THE ABC DOMAIN OF HLYB AND OTHER ABC PROTEINS: SEARCHING FOR REGIONS RELATING TO SPECIFICITY/IDENTITY
MODEL FOR SECRETION OF TYPE 1 ALLOCRITES
ACKNOWLEDGMENTS
Chapter 12: BACTERIAL MULTIDRUG RESISTANCE MEDIATED BY ABC TRANSPORTERS
INTRODUCTION
PROPERTIES OF LMRA AND HORA
STRUCTURAL CHANGES INDUCED BY NUCLEOTIDE BINDING OR HYDROLYSIS DETECTED BY ATR-FTIR SPECTROSCOPY
COUPLING OF ATP HYDROLYSIS TO DRUG TRANSPORT
CONCLUSIONS AND PERSPECTIVES
ACKNOWLEDGMENTS
Chapter 13: STRUCTURE AND FUNCTION OF OSMOREGULATED ABC TRANSPORTERS
INTRODUCTION
STRUCTURAL ANALYSIS OF OSMOREGULATED ABC TRANSPORTERS
SPECIFICITY OF OSMOREGULATED ABC TRANSPORTERS
OSMOTIC REGULATION OF EXPRESSION OF GENES ENCODING ABC TRANSPORTERS
OSMOTIC REGULATION OF ACTIVITY OF ABC TRANSPORTERS
CHALLENGES AND PERSPECTIVES
ACKNOWLEDGMENTS
PART IV: NON-MAMMALIAN EUKARYOTE ABC TRANSPORTERS
Chapter 14: INVENTORY AND EVOLUTION OF FUNGAL ABC PROTEIN GENES
INTRODUCTION
THE INVENTORY AND MOLECULAR ARCHITECTURE OF FUNGAL ABC PROTEINS
THE PLEIOTROPIC DRUG RESISTANCE (PDR) SUBFAMILY
THE MULTIDRUG RESISTANCE-RELATED PROTEIN MRP/CFTR SUBFAMILY
THE ALDP ADRENOLEUKODYSTROPHY PROTEIN SUBFAMILY
THE MDR SUBFAMILY
THE NON-TRANSPORTER YEF3/RLI SUBFAMILIES AND NON-CLASSIFIED ABC PROTEINS
EVOLUTIONARY RELATIONSHIPS OF ABC GENES IN FUNGI
TRANSCRIPTOMES AND YEAST ABC GENE MRNA PROFILES
ACKNOWLEDGMENTS
Chapter 15: FUNGAL ABC PROTEINS IN CLINICAL DRUG RESISTANCE AND CELLULAR DETOXIFICATION
INTRODUCTION
PLEIOTROPIC DRUG RESISTANCE ABC TRANSPORTERS IN FUNGI
GENETIC ANALYSIS AND PHENOTYPIC CHARACTERIZATION
SUBSTRATE SPECIFICITY AND MECHANISMS OF DRUG RECOGNITION BY FUNGAL ABC PUMPS
MUTATIONAL ANALYSIS OF YEAST ABC PUMPS AND STRUCTURE–FUNCTION RELATIONSHIPS
CELLULAR DISTRIBUTION, TRAFFICKING, MEMBRANE LOCALIZATION AND PROTEOLYTIC TURNOVER
FUNCTIONAL ASSAYS FOR YEAST ABC PUMPS MEDIATING DRUG RESISTANCE
HETEROLOGOUS EXPRESSION OF EUKARYOTIC ABC PUMPS AND FUNCTIONAL COMPLEMENTATION IN YEAST
CLINICAL RELEVANCE OF ABC PUMPS FROM FUNGAL PATHOGENS AND THERAPEUTIC STRATEGIES
REGULATION OF DRUG RESISTANCE GENES WITHIN THE YEAST PDR NETWORK
THE CROSSTALK BETWEEN PDR AND STRESS RESPONSES
THE PHYSIOLOGICAL FUNCTIONS OF YEAST ABC PUMPS
CONCLUSIONS AND PERSPECTIVES
ACKNOWLEDGMENTS
Chapter 16: DRUG RESISTANCE MEDIATED BY ABC TRANSPORTERS IN PARASITES OF HUMANS
INTRODUCTION
OCCURRENCE OF ABC TRANSPORTERS IN PARASITES
ROLE OF PARASITIC ABC TRANSPORTERS INCLUDING THEIR INVOLVEMENT IN DRUG RESISTANCE
CLINICAL IMPLICATIONS AND OUTLOOK
ACKNOWLEDGMENTS
Chapter 17: THE PLANT ABC TRANSPORTER SUPERFAMILY: THE FUNCTIONS OF A FEW AND IDENTITIES OF MANY
INTRODUCTION
SUBFAMILIES OF ARABIDOPSIS ABC PROTEINS
FULL-MOLECULE ABC TRANSPORTERS
HALF-MOLECULE TRANSPORTERS
‘SOLUBLE’ ABC PROTEINS
WHY SO MANY ABC PROTEIN GENES IN ARABIDOPSIS?
CONCLUDING REMARKS
ACKNOWLEDGMENTS
PART V: MAMMALIAN MULTIDRUG RESISTANCE ABC TRANSPORTERS
Chapter 18: SOLVING THE PROBLEM OF MULTIDRUG RESISTANCE: ABC TRANSPORTERS IN CLINICAL ONCOLOGY
INTRODUCTION
ABC TRANSPORTERS WITH POTENTIAL ROLES IN MULTIDRUG RESISTANCE
P-GLYCOPROTEIN (ABCB1) AS THE FIRST MDR TRANSPORTER TARGETED IN CLINICAL TRIALS
DETERMINING THE EXPRESSION OF DRUG TRANSPORTERS IN CANCER
EXPRESSION OF ABC TRANSPORTERS IN SELECTED MALIGNANCIES
P-GLYCOPROTEIN INHIBITORS AND PHARMACOKINETIC INTERACTIONS
REVERSAL OF DRUG RESISTANCE MEDIATED BY ABC TRANSPORTERS
PREVENTION OF DRUG RESISTANCE
CONCLUSION
Chapter 19: MULTIDRUG RESISTANCE PROTEIN 1 (ABCC1)
INTRODUCTION
PROPERTIES OF MRP1
CLINICAL RELEVANCE OF MRP1
Chapter 20: MRP2, THE APICAL EXPORT PUMP FOR ANIONIC CONJUGATES
INTRODUCTION
MOLECULAR CHARACTERIZATION OF THE APICAL CONJUGATE EXPORT PUMP MRP2
TISSUE DISTRIBUTION AND LOCALIZATION OF MRP2 IN POLARIZED CELLS
FUNCTIONAL ANALYSIS AND SUBSTRATE SPECIFICITY OF MRP2
DETOXIFICATION AND DRUG RESISTANCE CONFERRED BY MRP2
MUTATIONS IN THE MRP2 GENE
REGULATION OF MRP2 GENE EXPRESSION
CONCLUSIONS AND PERSPECTIVES
ACKNOWLEDGMENTS
Chapter 21: THE MULTIDRUG RESISTANCE PROTEINS 3–7
INTRODUCTION
MRP3
MRP4
MRP5
MRP6
MRP7
ACKNOWLEDGMENTS
PART VI: ABC TRANSPORTERS, PHYSIOLOGICAL ROLES AND HUMAN DISEASE
Chapter 22: LIPID TRANSPORT BY ABC TRANSPORTERS
INTRODUCTION
THE MDR1 (ABCB1) P-GLYCOPROTEIN AND ITS ROLE IN TRANSPORTING PHYSIOLOGICAL LIPIDS
TRANSPORT OF LIPID ANALOGUES BY ABC TRANSPORTERS
THE PC TRANSLOCATOR (MDR3, MDR2, ABCB4)
STEROL TRANSPORT BY ABC TRANSPORTERS
ACKNOWLEDGMENTS
Chapter 23: ROLE OF ABCA1 IN CELL TURNOVER AND LIPID HOMEOSTASIS
STRUCTURAL TRAITS OF ABCA1 AND RELATED TRANSPORTERS
THE IMPACT OF ABCA1 ON PHYSIOLOGICAL FUNCTIONS
ACKNOWLEDGMENTS
Chapter 24: PEROXISOMAL ABC TRANSPORTERS
INTRODUCTION
OVERVIEW OF PEROXISOME BIOLOGY
PEROXISOME ABC TRANSPORTERS
ACKNOWLEDGMENTS
Chapter 25: ABC TRANSPORTERS IN MITOCHONDRIA
INTRODUCTION
MITOCHONDRIAL ABC TRANSPORTERS IN S. CEREVISIAE
MITOCHONDRIAL ABC TRANSPORTERS IN MAMMALS
MITOCHONDRIAL ABC TRANSPORTERS IN PLANTS
FUTURE DIRECTIONS
ACKNOWLEDGMENTS
Chapter 26: THE TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING (TAP): A PEPTIDE TRANSPORT AND LOADING COMPLEX ESSENTIAL FOR CELLULAR IMMUNE RESPONSE
OVERVIEW OF THE MHC CLASS I ANTIGEN PROCESSING
THE TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING, TAP (ABCB2/ABCB3)
TAP AS A CENTRAL PART OF A MACROMOLECULAR PEPTIDE TRANSPORT AND CHAPERONE COMPLEX
VIRAL STRATEGIES OF IMMUNE EVASION
TUMOR ESCAPE STRATEGIES
CONCLUSIONS
Chapter 27: THE SULFONYLUREA RECEPTOR: AN ABCC TRANSPORTER THAT ACTS AS AN ION CHANNEL REGULATOR
INTRODUCTION
PHYSIOLOGICAL ROLE
MOLECULAR PROPERTIES
REGULATION BY NUCLEOTIDES
METABOLIC REGULATION OF THE KATP CHANNEL
EFFECTS OF OTHER KATP CHANNEL REGULATORS
PHARMACOLOGY
CONCLUSION AND PERSPECTIVES
GLOSSARY
ACKNOWLEDGMENTS
Chapter 28: ABC TRANSPORTERS AND HUMAN EYE DISEASE
INTRODUCTION
ABCA4 IN RETINAL DYSTROPHIES
ABCA4 IN AGE-RELATED MACULAR DEGENERATION (AMD)
FUNCTIONAL STUDIES OF ABCA4
ABCC6 AND PSEUDOXANTHOMA ELASTICUM
PERSPECTIVES
ACKNOWLEDGMENTS
Chapter 29: THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (ABCC7)
CFTR MUTATION CAUSES CYSTIC FIBROSIS
CFTR STRUCTURE
CFTR IS AN EPITHELIAL CHLORIDE CHANNEL
THE CFTR CHANNEL PORE
SER/THR PHOSPHORYLATION ACTIVATES THE CHANNEL
CFTR BINDS AND HYDROLYZES ATP
REGULATION OF CHANNEL GATING BY PURINE NUCLEOTIDES
CFTR MATURATION AND TRAFFICKING IN THE SECRETORY PATHWAY
Chapter 30: ABC PROTEINS, THE FASCINATION, THE POLITICS, THE POTENTIAL FOR APPLICATIONS FOR IMPROVING HUMAN HEALTH
THE FASCINATION
THE POLITICS
DIFFICULTIES, REALITIES AND PROSPECTS FOR APPLICATIONS
PREVENTION AND TREATMENTS OF DISEASE: THE MOLECULAR FUTURE
PERSPECTIVES
Index
