CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS

CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS CHAPTER 8 – INTRODUCTION TO BACTERIAL ABC PROTEINS

149 CHAPTER INTRODUCTION TO BACTERIAL ABC PROTEINS I BARRY HOLLAND In Chapter in this volume, E Dassa has reviewed the classification of ABC proteins, including prokaryote representatives and their transport substrates in the many cases where these have been identified Previous general reviews have also discussed the ABC proteins in Escherichia coli (Linton and Higgins, 1998), Bacillus subtilis (Quentin et al., 1999) and Mycobacterium tuberculosis (Braibant et al., 2000) and more specifically concerning bacterial ABC exporters in E coli (Fath and Kolter, 1993; Young and Holland, 1999) The purpose of this introductory chapter is therefore briefly to highlight some of the major characteristics of bacterial ABC systems and the breadth of their functions NATURE AND COMPOSITION OF THE ABC TRANSPORTER Prokaryote ABC-dependent transport systems, whether exporters or importers, all adhere to the usual formula of a basic four-unit structure, two membrane components and two units of ABC-ATPases The membrane components and the ABCs may be identical or non-identical and can be fused pairwise in different combinations as shown in Chapter 1, although unlike those commonly found in eukaryotes no examples of all four subunits fused together have been ABC Proteins: From Bacteria to Man ISBN 0-12-352551-9 identified in prokaryotes In describing ABCdependent transport systems, it is important to emphasize that the term ABC (ATP-binding cassette, Hyde et al., 1990) is synonymous with ABC-ATPase, whether present as a subdomain or an independent polypeptide The term ABC transporter, on the other hand, describes the ABC-ATPase (also called a traffic ATPase; Ames and Lecar, 1992) plus its associated integral membrane domains, whether fused to the ABC or separately encoded This core transporter or translocation complex may be further supplemented with essential accessory or auxiliary subunits (usually encoded separately): the external ligand-binding protein in the case of ABC importers, or the MFP (membrane fusion protein) and the OMP-F (outer membrane protein/factor) or OMA (outer membrane auxiliary) integral to the inner membrane and outer membrane, respectively In the case of ABC transporters, the whole complex may sometimes be referred to as the translocon, whilst for the importers, the term permease is also used to describe the entire complex Whilst ATP is the substrate for the ABCATPase, the molecule or ion being transported by the ABC transporter is variously described as a substrate or a transport substrate or an allocrite Since in our view, in the vast majority of cases, the component being transported remains unmodified by the process, the term ‘substrate’ is inappropriate, and we prefer allocrite, a term we coined, loosely derived from the Greek meaning a substance transported or Copyright 2003 Elsevier Science Ltd All rights of reproduction in any form reserved 150 ABC PROTEINS: FROM BACTERIA TO MAN exported (Blight and Holland, 1990; Young and Holland, 1999) AN ABUNDANCE OF DIFFERENT TYPES OF ABC PROTEINS IN PROKARYOTES Probably the earliest detailed studies of ABC proteins were carried out in bacteria in the 1970s and 1980s, concerning the mechanism of uptake of solutes such as histidine and maltose, mediated by the ABC proteins, HisP (Ames and Nikaido, 1978) and MalK (Bavoil et al., 1980) in Salmonella typhimurium and E coli, respectively These proteins were initially recognized as binding ATP and subsequently as energy generators for transport (Hobson et al., 1984; Shuman and Silhavy, 1981), through the hydrolysis of ATP As seen in Chapter 9, although we still have much to learn concerning the mechanism of transport driven by, for example, HisP and MalK, structural and genetic studies of the importing ABCs continue to be the most advanced ABC-ATPases are now recognized as one of the major superfamilies of proteins, represented in all three kingdoms of life and found in all organisms so far analyzed ABC proteins are particularly abundant in prokaryotes, with genes constituting from close to 1% and up to more than 3% amongst the 19 eubacteria and archaea, respectively, surveyed in Chapter The very recent sequence of the Agrobacterium tumefaciens genome describes the highest number recorded so far, 153, excluding orphan ABCs (with no discernible membrane domain associates) Thus, ABC transporters constitute 60% of all transporters and about 3% of all predicted polypeptides in the A tumefaciens genome (Goodner et al., 2001; Wood et al., 2001) All the known bacterial genomes, with one exception, Treponema pallidum (only 1.14 Mb), encode all the three main categories of ABC protein discussed below, the exporters, orphans and importers Curiously, T pallidum and four out of the six archaeal genomes listed in Chapter 1, apparently not encode any exporters In Chapter 1, based on cluster or phylogeny analysis of sequences constituting the ABC polypeptides, over 600 examples out of the more than 2000 entries in the current databases, 33 distinct clusters were identified These are assigned so far to three major classes, all strongly represented in bacteria Class contains the large family of exporters Class is a small family of orphans, with no known membrane protein associates and, at least in some cases, with no connection to membrane transport processes, for example the bacterial UvrA protein essential for specific DNA repair processes Class is functionally probably a more heterogeneous family, since it probably contains both importers and exporters This heterogeneity may necessitate a future separation into at least two distinct classes AN ADDITIONAL CLASS OF BACTERIAL ABCS INVOLVED IN DNA RECOMBINATION AND REPAIR Importantly, an additional important group of ABC proteins present in both bacteria and eukaryotes, which are not involved in transport but concerned with DNA repair or recombination, have yet to be classified as class 1, or and may well constitute a completely new class Such an example, the ABC domain of Rad50 from Pyrococcus furiosus, involved in homologous recombination, has recently been crystallized and the structure determined (Hopfner et al., 2000) The ABC domain contains the two characteristic lobes or arms found in HisP (Hung et al., 1998) This contains all the expected, highly conserved motifs, the Walker A, Q-loop, Walker B and the downstream histidine (Linton and Higgins, 1998), present in Arm-I, the RecA-like, catalytic domain (Geourjon et al., 2001) Similarly, Rad50 contains the signature motif in the smaller Arm-II, sometimes referred to as the helical (Ames and Lecar, 1992) or signaling/regulatory domain (Holland and Blight, 1999) In reality, in the intact Rad50 molecule, the helical or signaling domain is interrupted by the insertion into helix of 600 residues forming a long coiled coil region, thereby separating the Walker A from the Walker B domain Interestingly, as discussed in Chapter 11, structural studies so far indicate that functionally different types of ABC protein display the greatest variation in INTRODUCTION TO BACTERIAL ABC PROTEINS structural organization in the helical domain, frequently affecting helix The extensive coiled coil region of Rad50, facilitating dimerization of these large molecules, restoring the close proximity of the Walker A and B motifs for nucleotide binding, is in fact diagnostic of a large family of bacterial and eukaryote SMC (structural maintenance of chromosome) proteins (Melby et al., 1998; Soppa, 2001), many of which are involved in condensation of DNA, including the SMC protein in B subtilis required for chromosomal segregation (Graumann et al., 1998) Notably, whereas Rad50 has a relatively well-conserved LSGG motif compared with the ‘classical’ ABC proteins, other SMCs have a more ‘degenerate’ version of this signature motif Finally, perhaps the most distant relatives, but still considered as ABC proteins (Aravind et al., 1999), are the DNA repair enzymes such as the bacterial MutS These proteins contain minimal Walker A and B motifs and have the same overall fold for the catalytic domain as HisP (Lamers et al., 2000), but the signature motif is significantly diverged from that of HisP, and indeed much of the region equivalent to the helical domain of HisP is absent (Geourjon et al., 2001) EXPORTERS Class ABC-ATPases (fused to a membrane domain), and apparently some class proteins (encoded independently from the membrane domain), constitute at least eight distinct families, all concerned with the export of a wide range of compounds These include extremely large polypeptides, greater than 400 kDa in some cases (Chapter 11), polysaccharides, a wide variety of antibiotics, many drugs (Chapter 12), and certain lipids (Chapter 7) A fascinating adaptation of the modular structure of an ABC protein is shown in the ABC component of the translocators for non-lantibiotics secreted by Gram-positive bacteria In these cases the N-terminal domain of the ABC transporter carries a cytoplasmic extension to the membrane domain (Havarstein et al., 1995), which constitutes a cysteine protease, necessary for processing the antibiotic peptide as it exits from the cell (see Chapter 11) Some evidence suggests that class ABCs are also involved in exporting fatty acids and Naϩ ions as transport substrates or allocrites As reviewed in Chapter 1, however, firm evidence for the identity of allocrites in many cases is still lacking Importantly, whilst inferences regarding potential allocrites for class transporters can be drawn from cluster analysis through guilt by association with well-characterized transporters, this approach is not necessarily reliable One of the largest exporter families, DPL (see Chapter 1), contains at least 11 subfamilies of bacterial ABCs, which are involved in the export of allocrites as diverse as lipids, large polypeptides, or a wide range of drugs Of course, we cannot rule out the possibility that some of these transporters export in reality more than one type of compound, as has been demonstrated for Pgp (Johnstone et al., 2000; Raymond et al., 1992) As a further complication, the ABC transporters in the Prt and Hly clusters in the heterogeneous DPL family require additional, specific auxiliary membrane proteins in order to complete, if not provide, the actual translocation pathway (Chapter 11) Interestingly, from knowledge that is available so far, the bacterial exporters appear to fulfill a variety of important cellular functions, for example the secretion of factors required for dominating other bacterial species in the environment, for colonization of plant, insect or animal hosts leading to pathogenic infection or symbiosis, for the removal of toxic compounds and for the biogenesis of several constituents of the organism’s own cellular envelope Many of the latter are essential for respiratory functions, the integrity of the bilayer, simple surface protection and even movement of the bacteria Moreover, some ABC exporters have been implicated in various developmental and differentiation programs, although their precise roles and allocrites transported in these cases are mostly obscure For further information and literature sources on several of these aspects, see other chapters in Parts I and II in this volume CLASS 2, ORPHAN ABCS The class group of ABC proteins are present in all organisms but are curious exceptions to the rule that the ABC proteins are always involved in transport processes across membranes The functions of these proteins as a group are quite diverse and surprising, being involved in translation of polypeptides, drug and antibiotic resistance, and in DNA repair, although only the latter two have been documented in bacteria so far (Chapter 1) It is intriguing to know what 151 152 ABC PROTEINS: FROM BACTERIA TO MAN common principles might govern the action of a highly conserved ABC domain involved in processes as different as membrane transport, DNA repair and protein synthesis Interestingly, in the bacterial UvrA protein, a tandemly duplicated ABC, there is an insertion of a DNA binding motif, a zinc finger, between the Walker A and the signature motif in each ABC domain (see, for example, Husain et al., 1986; Yamamoto et al., 1996) This insertion occurs in a position close to the equivalent of the interface between the two lobes in the HisP structure, which presumably must affect the regulation of UvrA function As a further curiosity, if not a mystery, ABCs in this group of class orphans include proteins, also with duplicated ABC domains, from, for example, Staphylococcus aureus and Streptomyces antibioticus (Mendez and Salas, 2001; Ross et al., 1995), responsible for resistance (and immunity in some cases) to certain drugs and antibiotics The simplest explanation would be that these ABCs work in conjunction with some membrane protein to export the drugs but, despite intensive efforts, such proteins have not yet been identified IMPORTERS The class ABC transporters in bacteria constitute an enormous family of import systems for small molecules The transport complex is composed of two molecules of an independently encoded ABC protein(s), a hetero- or homodimer of integral membrane proteins constituting the translocation pathway, and an external ligandbinding protein, amongst which the most characterized, the periplasmic binding proteins in Gram-negative bacteria are considered in Chapter 10 The class importers have been assigned to at least nine major families in the phylogeny analysis in Chapter The allocrites transported cover a wide range of essential and non-essential molecules, including several metal ions, iron chelates, vitamin B12, mono-, di- and oligosaccharides, polyols, polyamines, inorganic anions such as sulfate, nitrate and phosphate, phosphonates, peptide osmoprotectants and ssother di- and oligopeptides From these examples, the import systems for histidine and maltose will be considered in some detail in Chapter 9, and for uptake of osmoprotectants in Chapter 13 As already indicated, despite the range of allocrites transported in this very large family, the nature of the different translocators is surprisingly uniform: an external ligand-binding protein, free in the periplasm in Gram-negative bacteria whilst it may be anchored to the membrane surface in Gram-positive bacteria; two membrane proteins for transport, carrying the EAA interaction motif; and a highly conserved ABC protein on the cytoplasmic side of the inner membrane Since evidence of exchangeability of one ABC component for another in these otherwise very similar systems has been rarely indicated in the literature, we must assume that each ABC is tailormade for contact and intramolecular signaling with its cognate membrane domains Recent studies of two ABC-dependent solute uptake systems responsible for transport of general amino acids and branched amino acids in Rhizobium leguminosarum have revealed the surprising finding that such systems can apparently also export these amino acids Moreover, the same phenomenon was demonstrated with histidine transport in S typhimurium (Hosie et al., 2001) This reverse transport or bidirectional capacity of these ABC transporters raises some complex questions concerning the solute pathway in the two different directions In addition, it is not yet clear whether ATPase activity is required for the efflux process (P Poole, personal comunication) MEMBRANE DOMAINS OF THE BACTERIAL TRANSPORTERS ARE POORLY UNDERSTOOD Whereas great progress has been made in the comparative, phylogenic analysis of the ABC domains, leading to prediction of possible function in the absence of other evidence in many cases, the cluster analysis of membrane domains has lagged far behind This clearly hampers insights into the mechanistic role of these domains as potential translocation pathways and these are poorly understood Nevertheless, as discussed in Chapter 9, the early recognition (Dassa and Hofnung, 1985) of the EAA motif, apparently completely conserved without exception within a cytoplasmic loop of the membrane components of all the bacterial ABC importers, has ultimately led to the identification of this as a specific point of contact with a region of the helical domain of the ABC-ATPase INTRODUCTION TO BACTERIAL ABC PROTEINS This is presumably also a critical point in the intramolecular signaling pathway, coordinating transport and energy generation Importantly, the EAA motif is not present in any of the exporters, indicating that during evolution ABC-ATPases, in bacteria at least, have associated with more than one type of membrane domain Furthermore, the failure so far to detect any kind of conserved motif in the membrane domains of ABC exporters perhaps emphasizes, in contrast to the importers, the wide variation in both the mechanism and the pathway of molecular signaling between the membrane and ABC components of the exporters As indicated below and discussed in Chapter 7, the elucidation of the structure of the membrane domain of the E coli MsbA protein will now enormously stimulate this aspect of ABC studies STRUCTURE AND FUNCTION OF THE ABC TRANSPORTERS Notably, some of the most advanced structural studies of ABC transporters have come from bacterial import and, more recently, bacterial export systems Thus, we now have high-resolution structures for ABC importers, HisP (Hung et al., 1998), a MalK from Thermococcus litoralis (Diederichs et al., 2000), one ABC in the family of branched-chain amino acid transporters and one of unknown function (Karpowich et al., 2001; Yuan et al., 2001) In this laboratory, we have recently obtained the high-resolution structure of the ABC domain of HlyB (Schmitt et al., in preparation), a member of the large DPL family, which includes the mammalian TAP and Pgp (Mdr1) proteins The implications of all these structural advances will be considered in other chapters As discussed in Chapter 7, a very major and exciting advance in the field was made by the presentation of the first structural data at 4.5 Å for the intact bacterial exporter MsbA from E coli (Chang and Roth, 2001) This provides the first sign of the nature of the membrane domain, and, in particular, that of the membrane-spanning domains These are finally shown to be helices, settling some previous controversies Most crucially, of course, this overall structure of MsbA has profound implications for at least a global understanding of how the action of the membrane and ABC domains may be coordinated Chang and Roth (see also Higgins and Linton, 2001) on the basis of this structure have already proposed an exciting solution to a long-standing puzzle – how close are the ABC domains in the transporter? – that most likely they are interfaced at some point in the catalytic cycle (see also Chapter 6), but under the influence of the membrane domains they are well separated in the absence of any transport substrate Unfortunately, mechanistic 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