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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