Res. Microbiol. 152 (2001) 205–210
 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0923-2508(01)01193-7/REV
Overview
ABC transporters: physiology, structure and mechanism – an overview
Christopher F. Higgins∗
MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK
Received 26 January 2001; accepted 12 February 2001
Abstract – ABC transporters form one of the largest of all protein families with a diversity of physiological functions.
In Escherichia coli almost 5% of the genome is occupied by genes encoding components of these transporters, and there
are examples in all species from microbes to man. In this overview, the importance of studies on bacteria in elucidating
many basic principles pertaining to ABC transporters is emphasised. The family is described and a general overview of
the structure and function of these transporters is presented.  2001 Éditions scientifiques et médicales Elsevier SAS
ABC transporters / mechanisms / structure / binding proteins
1. Historical background
ABC (ATP binding cassette) transporters comprise
one of the largest of all paralogous protein families.
Almost 5% of the entire Escherichia coli genome encodes components of ABC transporters [27]. ABC
transporters are found in all species from the lowliest microbe to man, play a wide variety of physiological roles, and are of very considerable medical
and economic importance. In microorganisms ABC
transporters are central to antibiotic and antifungal resistance, and in man many are associated with genetic
diseases including cystic fibrosis, Tangier disease, obstetric cholestases, and drug resistance of cancers. Although ABC transporters are now ‘high profile’, it is
frequently forgotten that they were first identified and
characterised in model bacteria where the majority of
fundamental principles relating to structure and function were developed.
The physiology of transport systems mediating the
uptake of nutrients by bacteria (particularly E. coli
and Salmonella typhimurium) was studied in detail in
the 1970s. It soon became apparent that bacteria had
multiple systems for the uptake of most nutrients and
that these systems fell into a small number of classes:
the phosphotransferase systems; secondary, shockinsensitive transporters energised by the electrochem-
∗ Correspondence and reprints.
E-mail address: [email protected]
(C.F. Higgins).
ical gradient; and primary, shock-sensitive systems
energised directly by the hydrolysis of ATP [4]. This
latter class of transporter was sensitive to osmotic
shock due to the loss of a substrate-binding protein
from the periplasm (hence the term periplasmic binding protein-dependent transport systems).
In 1982 the first complete sequence of the genes
encoding one of these periplasmic transporters, the
histidine transporter of S. typhimurium, was published [15]. In addition to the periplasmic substratebinding protein (HisJ), the transporter has three
membrane-associated components (HisQMP). Shortly
thereafter, the sequence of a component of the E. coli
maltose transporter (MalK) was determined and its
sequence similarity to HisP led to the suggestion
that such transporters might have evolved from a
common ancestor [13]. When the sequence of a
third homologue, OppD from the oligopeptide transporter of S. typhimurium, was obtained it was noted
that these proteins included a consensus nucleotidebinding motif [16], similar to that previously identified in ATP synthase, myosin and adenylate kinase [38]. This led to the suggestion that these domains couple ATP hydrolysis to the transport process.
Experimental evidence that these domains bind ATP
[16, 20] and that ATP hydrolysis is coupled to transport [5, 29] soon followed.
In 1986, it was recognised that the ATP binding
subunits from bacterial transporters defined a large
superfamily family of proteins and the core organisation of four domains (see below) was proposed [17].
Although the majority of these domains were clearly
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C.F. Higgins / Res. Microbiol. 152 (2001) 205–210
components of active transport systems, it was noted
that some were ‘orphans’ and had probably been recruited to couple ATPase activity to other biological
processes such as DNA repair [11, 17]. 1986 also
saw identification of the first eukaryotic example of
this family of transporter, the human multidrug resistance P-glycoprotein [7, 12, 14]. The name ABC
(ATP binding cassette) transporter was coined in 1990
[24], cementing a general recognition of the importance of this evolutionarily related but functionally diverse family of proteins.
2. Diversity of substrate specificity
and physiological roles
The number of ABC transporters differs widely
between species. Organisms such as E. coli, which
live in diverse environments and need to adapt to a
great array of external conditions, have many; around
70 ABC transporters are encoded by the E. coli
chromosome [27]. In contrast, some other species
have far fewer examples, perhaps reflecting their
restrictive lifestyles (Dassa, this issue).
Although, in general, each ABC transporter is relatively specific for its own particular substrate(s), it is
remarkable that there is an ABC transporter for essentially every type of molecule that must cross a cellular
membrane. ABC transporters have been characterised
with specificity for small molecules, large molecules,
highly charged molecules and highly hydrophobic
molecules–systems are known with specificity for inorganic ions, sugars, amino acids, proteins, and complex polysaccharides. Although most exhibit relatively tight substrate specificity, some are multispecific such as the oligopeptide transporter which handles essentially all di- and tripeptides [35], and some
have an extremely broad specificity for hydrophobic compounds, such as the multidrug transporter
LmrA from Lactococcis lactis [36]. It is intriguing
how these related transport proteins can accommodate such diversity.
The diversity in substrate specificity is reflected in
the diversity of physiological roles played by ABC
transporters in the cell. Although the ABC transporters first characterised were nutrient uptake systems, it is now clear that many ABC transporters are
exporters. Many of these play roles in elimination of
waste products or toxins from the cell such as the
LmrA protein of Lactococcus lactis (van Veen et al.,
this issue) and ABC transporters in fungi which confer resistance to antifungal agents (Wolfger et al., this
issue). Other ABC transporters are essential for the
export of cellular components which function outside
the plama membrane including cell wall polysaccharides (Silver et al., this issue), in cytochrome c biogenesis (Goldman and Kranz, this issue), and antibiotic production (Mendez and Salas, this issue). Many
polypeptides required outside the cell, such as cellulases, proteinases, or toxins such as haemolysin, are
also exported via dedicated ABC transporters rather
than the general signal peptide-dependent protein secretory pathway.
Finally, it should be emphasised that a few ‘apparent’ ABC transporters appear to have diversified
in function (reviewed in [18]). In the mammalian
world, the cystic fibrosis protein, which to all intents
and purposes looks like a typical ABC transporter, is
not a transporter; it is a chloride channel. Potentially,
some microbial ABC transporters may also be channels rather than transporters. In addition, some ABC
‘transporters’ serve a regulatory rather than transport
function. The best characterised example is the mammalian sulphonyl urea receptor (SUR) which has no
known transport activity but imposes nucleotide regulation on a heterologous potassium channel [1]. Such
a regulatory role is best exemplified in the bacterial
world by the Sap/Trk system of S. typhimurium/E.
coli which regulates a potassium channel independently of any transport activity it may or may not
have [30, 34]. The mechanisms, though likely involving protein-protein interactions within the membrane,
are obscure.
3. Organisation and structure
The basic unit of an ABC transporter consists of
four core domains [17, 24]. Frequently, each of the
four core domains is encoded as a separate polypeptide (e.g., the oligopeptide transporter; [19], although
in other transporters the domains can be fused in any
one of a number of ways into multidomain polypeptides (figure 1). In cases in which one of the four domains appears to be absent, one of the remaining domains functions as a homodimer to maintain the full
complement [9, 26].
The two transmembrane domains (TMDs) span
the membrane multiple times via putative α-helices.
Typically, there are six predicted membrane-spanning
C.F. Higgins / Res. Microbiol. 152 (2001) 205–210
Figure 1. Organisation of ABC transporters. The typical ABC
transporter has four domains, two membrane-associated domains
(TMDs) are depicted by shaded squares. The two ATP-binding
domains (NBDs or ABC domains) are depicted by ovals at the
intracellular face of the membrane. The domains can be fused
in any one of a number of ways: (A) they can be encoded as
four separate polypeptides (as for the oligopeptide transporter
OppBCDF); (B) fused NBDs (as for the ribose transporter RbsA);
(C) fused TMDs (as for the iron-chelate transporter FhuCB); (D)
one ABC fused to one NBD, with the hybrid protein functioning as
a homodimer (as for LmrA); (E) one TMD fused to one NBD, with
the other TMD and NBD as separate polypeptides (as for YhiGHI
of E. coli ); (F) all four domains fused into a single polypeptide,
often found in eukaryotic ABC transporters. From Linton and
Higgins, Molecular Microbiology 28 (1998) 5–13.
α-helices per domain (a total of twelve per transporter) although there is some variation on this formula. Some of the predicted membrane-spanning αhelices may not be crucial to the core function of the
transporter but may serve auxillary functions such as
membrane insertion or regulation. The TMDs form
the pathway through which solute crosses the membrane and determine the specificity of the transporter
through substrate-binding sites.
The other two domains, the ATP or nucleotidebinding domains (NBDs), are hydrophilic and peripherally associated with the cytoplasmic face of the
membrane. These domains consist of the core 215
or so amino acids of the ABC domain by which
these transporters are defined. It is important to emphasise that it is the conservation of this entire domain which is important in defining and delimiting
the family [17]; other ATP-binding proteins which
are not ABC transporters can include the Walker A
and Walker B motifs. Although it has been suggested
that the NBDs may span the membrane [3], more recent data now suggest this is unlikely and that they
are not exposed extracellularly [6]. The crystal structures of several isolated ABC domains have now been
determined and the structures of HisP, MalK, RbsA
and the eukaryotic Rad50 published [2, 10, 21, 22],
207
all of which (not unexpectedly) show very similar
folds. However, the various structures differ significantly in the dimer interface such that, even though it
seems likely that the ABC domains do interact, the
residues or faces of the domains involved in such
interactions are unknown. Similarly, it remains unclear which faces of the NBDs interact with the transmembrane domains. Although some data pertaining
to the residues involved in domain-domain interactions have been obtained (Schneider, this issue), the
precise nature of these interactions remains to be determined.
In many ABC transporters auxillary domains have
been recruited for specific functions. The periplasmic
binding proteins (PBPs) bind substrate external to
the cell and deliver it to the membrane-associated
transport complex. In Gram-positive bacteria, which
lack an outer membrane (and hence periplasm), the
equivalent substrate binding proteins are anchored to
the outside of the cell via lipid groups [31]. It appears
that PBPs may have two distinct but related functions.
(a) The first is to impart high affinity and specificity. An initial distinction between PBP-dependent
and other transporters was that the PBP transporters
showed remarkably high affinity. Similarly, most
ABC transporters which lack a PBP (eg drug transporters) have rather broad specificity while those with
a PBP can be highly specific. It is unclear why a PBP
is apparently important for conferring high specificity
and affinity – perhaps flexibility in the TMDs necessary for their transport function (see below) precludes
the ‘lock and key’ fit required.
(b) The second is to confer directionality. There is a
100% correlation, at least for those systems analysed
in detail, between the presence of a PBP and solute
uptake, and between the absence of a PBP and solute
export. Although this does not prove that the PBP
determines directionality, the fact that interaction of
the PBP with the transporter at the outside of the cell
can trigger ATP hydrolysis at the cytoplasmic face of
the membrane strongly implies such a role [8].
Other ABC transporters require outer membrane
proteins to facilitate solute entry into the periplasm
(eg transporters for iron chelates), while Gram-negative ABC transporters which mediate protein export
require additional outer membrane proteins to facilitate transport across the periplasm and outer membrane (eg the HlyD and TolC proteins required for export of haemolysin [25]. No doubt other ABC trans-
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C.F. Higgins / Res. Microbiol. 152 (2001) 205–210
ever, consistent with the fact that some ABC transporters can transport very large substrates, an observation difficult to reconcile with tightly packed αhelices. Second, in ABC transporters the NBDs are
in close association with the TMDs, rather than being separated by ‘stalks’ as in the F1F0 ATPase or
Ca2+ ATPase. The significance of this is unknown.
Although these structural data have implications for
the mechanisms of transport (see below), the absence
of a high resolution structure of the TMDs limits our
understanding of how ABC transporters work.
4. Mechanisms of transport
Figure 2. Structure of ABC transporters. The overall structure
of an ABC transporter is shown diagramatically, based on the
structure of the mammalian P-glycoprotein ([32] and Rosenberg
et al., submitted for publication). The protein consists of an
aqueous pore, formed by the TMDs, with a large opening at the
extracellular face of the membrane. The NBDs (light blue) are at
the cytoplasmic face of the membrane in close apposition to the
TMDs and possibly party buried in the lipid bilayer though not
spanning the membrane. Diagram courtesy of Mark Rosenberg
and Bob Ford.
porters with peripheral or auxillary proteins will be
identified.
Although the structures of several ABC domains
have now been elucidated, the overall structure of an
intact ABC transporter has been very difficult to obtain. Here the microbial field can learn from the eukaryotic field. The structure of the mammalian multidrug resistance P-glycoprotein has been determined
to 25 Å by single particle imaging [32], and to close to
10 Å by 2-D cryoelectron microscopy (Rosenberg et
al., submitted for publication). Briefly (figure 2), the
TMDs form a large ring-like chamber in the membrane, with an opening to the extracellular milieu and
closed at the cytoplasmic face of the membrane. The
NBDs are located at the cytoplasmic face of the membrane in tight apposition to the membrane domains.
This structure is consistent with biochemical and genetic data for other ABC transporters and it seems
likely it reflects a general architecture for ABC transporters. The structure differs from other membrane
translocating ATPases, such as the Ca2+ -ATPase and
FI Fo ATPase in two important ways. First, the TMDs
form a large pore in the membrane as opposed to the
putative α-helices being tightly packed; this is, how-
The detailed mechanisms by which ABC transporters move solute across the cell membrane are still
far from clear. However, an overall picture is now
emerging based upon studies of both prokaryotic and
mammalian systems, making the not unreasonable assumption that there are mechanistic similarities. In
summary:
The transport cycle is initiated by the interaction of
substrate with the TMDs from the intracellular face
of the membrane (or inner leaflet of the lipid bilayer).
For importers the substrate can be considered as the
PBP-substrate complex interacting at the extracellular
face of the membrane. The substrate is then released
from the PBP to interact with the TMDs. The number
of substrate-binding sites on the TMDs is still unclear,
although is likely to be two [36]. Substrate binding
induces a conformational change in the TMDs which
is transmitted to the NBDs to initiate ATP hydrolysis. It is clear that both NBDs are required, and both
must hydrolyse ATP. However, they do so by an ‘alternating catalytic cycle’ mechanism [33] in which
only one NBD hydrolyses ATP at a time. It is unclear how many ATP molecules are hydrolysed per
molecule of substrate transported, and this is crucial
to complete elucidation of the transport cycle. However, it appears to be 1 to 2 [29], consistent with a
stoichiometric, closed cycle. Estimates of a greater
number of ATP molecules hydrolysed per transport
cycle, based on purified components, probably reflect
‘uncoupling’ of hydrolysis from transport. ATP hydrolysis induces further conformational changes in
the NBDs (e.g., [23, 28]) which is transduced to the
TMDs (Rosenberg et al., submitted for publication).
How do these conformational changes lead to
solute translocation? It now appears that transport in-
C.F. Higgins / Res. Microbiol. 152 (2001) 205–210
volves more-or-less conventional enzyme like mechanisms. For exporters, a high-affinity substrate binding
site at the inside of the membrane is reorientated to
be exposed to the outside of the membrane; simultaneously its affinity is reduced, resulting in extracellular release of the substrate (presumably for importers
the PBP induces a reversal of this process). Finally,
the transporter must be reset and the binding site reorientated back to the inside of the membrane and
affinity restored. It has been proposed that the transporters have two binding sites, one high affinity and
intracellular and the other low affinity and extracellular: the two alternate in affinity and sidedness in a
‘two-cylinder engine’ model ([37] and van Veen et al.,
this issue). It should be emphasised that the reorientation of a binding site does not necessarily mean a
large ‘movement’ of the site across the bilayer. More
probably the ‘site’ remains at the intracellular face of
the membrane and the conformational changes simply serve to alter its exposure to the intracellular milieu or the aqueous pore (extracellular) of the transporter.
In conclusion, it now seems clear that both the
ATP hydrolytic by the NBDs and reorientation and
changes in affinity of substrate binding sites (on the
TMDs the transport cycle) are conventional enzymelike processes. Precisely how the two are coupled, and
the nature of the conformational changes involved,
remain to be elucidated.
5. Conclusions
The importance of ABC transporters in cell physiology and medicine cannot be underestimated, and
ABC transporters are now recognised amongst the
most important of all protein families. The study of
ABC transporters, in all their guises, has now become a minor industry. This is a far cry from ‘orphan’ beginnings, and provides a wonderful example
of scientific serendipity, how fundamental studies of
obscure model microbial processes, pretty much for
their intrinsic interest with no obvious commercial or
medical implications, can unexpectedly have a significant impact in unimagined arenas of biology. As
with many areas of research, studies on ‘high profile’
eukaryotic systems could not have proceeded apace
without the fundamental advances derived from studies on microorganisms.
209
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