ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily which
uses the hydrolysis of ATP to energize diverse biological import and export
systems (see <PDOC00185>). ABC transporters are minimally constituted of two
conserved regions: a highly conserved ATP binding cassette (ABC) and a less
conserved transmembrane domain (TMD). These regions can be found on the same
protein (mostly in eukaryotes and bacterial exporters) or on two different
ones (mostly bacterial importers) [1,2,3]. The function of the integral
inner-membrane protein is to translocate the substrate across the membrane.
Studies of P-glycoprotein function indicate that residues lining the proposed
chamber opening (residues of TM2, TM5 and TM6) play an important role in
substrate recognition [4].
In exporters and eukaryotes, ABC transporters consist of a single polypeptide
composed of an N-terminal domain of approximately 320 residues, apparently
containing six transmembrane segments, fused to a highly conserved ABC-ATPase
domain of approximately 260 residues [5,6,7]. In some cases an N-terminal
peptidase domain of 130-150 residues appended to the TMD is also found, which
may contain additional transmembrane segments as in the HlyB subfamily [8,9].
The 3D structure of the E. coli lipid A flippase MsbA homodimer reveals that
association of the two transmembrane domains forms one chamber that adopt a
cone-shape which extends along a pseudo two-fold axis perpendicular to the
cell membrane (see <PDB:1JSQ>) [10]. The chamber has an opening on either side
of the membrane to provide free access for the lipid substrate from the
cytoplasmic leaflet of the lipid bilayer, while excluding molecules from the
outer leaflet. The chamber openings are defined by intramolecular interactions
between TM2 of one monomer and TM5 of the other. The residues lining the
chamber are contributed by all 12 transmembrane α-helices [10,11].
In importers (found only in prokaryotes or archaea) most ABC transporters
consist of four domains usually encoded by independent polypeptides, two ABC
modules and two TMDs which are thought to contain six transmembrane regions
[12,13]. The approximately 30 kD TMD displays a distinctive signature, the EAA
motif, a 20 amino acid conserved sequence located about 100 residues from the
C-terminus. The motif is hydrophilic and has been found to reside in a
cytoplasmic loop located between the penultimate and the antepenultimate
transmembrane segment in all proteins with a known topology [14,15,16]. It
appears to play an important role in ensuring the correct assembly of the
prokaryotic ABC transport complex [17] and constituting an interaction site
with the so-called helical domain of the ABC module [18,19]. The TMDs form
either homo-oligomeric channels or associate with another TMD to form
hetero-oligomers.
The 3D structure of the E. coli BtuCD proteins has been solved [20]. It
consists of two copies of the transmembrane domain BtuC and two copies of the
ATPase BtuD (see <PDB:1L7V>). Each BtuC subunit is composed of 10
α-helices, rather than the six of MsbA, and these are packed together in a
more intricated manner than MsbA. Helices two-five and seven-ten are related
by a pseudo-two-fold rotation axis, while helices one and six are nearly
perpendicular to the plane of the membrane. The prominent cytoplasmic loop
between helices six and seven folds into two short helices, L1 and L2, which
make extensive contacts with BtuC. The conserved sequence within the L1-L2
region may represent a general interface between the TMD and NBD [11,20].
During the transport cycle a conformational change involved by the NBD domain
has been described for this two kinds of transmembrane domains like those of
Pgp and MalFGK2 complex [21,22].
Integral membrane components of ABC complex have been shown to be evolutionary
related and proteins known to belong to this family are classified in several
functional subfamilies depending on the substrate used [E1]. All different
types of transporters with a functional attribution are listed below
(references are only provided for recently characterized proteins).
ALDP, a peroxisomal protein involved in X-linked adrenoleukodystrophy.
Antigen peptide transporters 1 (TAP1, PSF1, RING4, HAM-1, mtp1) and 2
(TAP2, PSF2, RING11, HAM-2, mtp2), which are involved in the transport of
antigens from the cytoplasm to a membrane-bound compartment for
association with MHC class I molecules.
Cystic fibrosis transmembrane conductance regulator (CFTR), which is most
probably involved in the transport of chloride ions.
Drosophila proteins white (w) and brown (bw), which are involved in the
import of ommatidium screening pigments.
Fungal elongation factor 3 (EF-3).
Multidrug transporters (Mdr1) (P-glycoprotein), a family of closely
related proteins which extrude a wide variety of drugs out of the cell.
70 Kd peroxisomal membrane protein (PMP70).
Sulfonylurea receptor, a putative subunit of the B-cell ATP-sensitive
potassium channel.
We have developed two profiles to distinguish between these two kinds of ABC
transmembrane domains. The first one recognizes the TMD in protein families
where TMD and NBD are on separate proteins. The second one picks up proteins
where TMD and NBD are fused. Both profiles cover the entire six transmembrane
region.
Note:
These profiles replace a pattern (PS00402) whose specificity was
inadequate.
Last update:
November 2003 / Pattern removed, profiles added and text revised.
The NodL and NodJ proteins from Rhizobium and Bradyrhizobium strains are similar to capsular polysaccharide secretion proteins from gram-negative bacteria.
Processing of colicin V-1, a secretable marker protein of a bacterial ATP binding cassette export system, requires membrane integrity, energy, and cytosolic factors.
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and
distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives
(CC BY-NC-ND 4.0) License, see prosite_license.html.
