ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily which
uses the hydrolysis of ATP to energize diverse biological systems. 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 or on two different
ones. Most ABC transporters function as a dimer and therefore are constituted
of four domains, two ABC modules and two TMDs [1].
ABC transporters are involved in the export or import of a wide variety of
substrates ranging from small ions to macromolecules. The major function of
ABC import systems is to provide essential nutrients to bacteria. They are
found only in prokaryotes and their four constitutive domains are usually
encoded by independent polypeptides (two ABC proteins and two TMD proteins).
Prokaryotic importers require additional extracytoplasmic binding proteins
(one or more per systems) for function. In contrast, export systems are
involved in the extrusion of noxious substances, the export of extracellular
toxins and the targeting of membrane components. They are found in all living
organisms and in general the TMD is fused to the ABC module in a variety of
combinations. Some eukaryotic exporters encode the four domains on
the same polypeptide chain
[1].
The ABC module (approximately two hundred amino acid residues) is known to
bind and hydrolyze ATP, thereby coupling transport to ATP hydrolysis in a
large number of biological processes. The cassette is duplicated in several
subfamilies. Its primary sequence is highly conserved, displaying a typical
phosphate-binding loop: Walker A, and a magnesium binding
site: Walker B. Besides these two regions, three other conserved motifs are
present in the ABC cassette: the switch region which contains a histidine
loop, postulated to polarize the attaching water molecule for hydrolysis, the
signature conserved motif (LSGGQ) specific to the ABC transporter, and the
Q-motif (between Walker A and the signature), which interacts with the gamma
phosphate through a water bond. The Walker A, Walker B, Q-loop and switch
region form the nucleotide binding site
[7][2][6].
The 3D structure of a monomeric ABC module adopts a stubby L-shape with two
distinct arms. ArmI (mainly beta-strand) contains Walker A
and Walker B. The important residues for ATP hydrolysis and/or binding are
located in the P-loop. The ATP-binding pocket is located at the extremity of
armI. The perpendicular armII contains mostly the alpha helical subdomain with
the signature motif. It only seems to be required for structural integrity of
the ABC module. ArmII is in direct contact with the TMD. The hinge between
armI and armII contains both the histidine loop and the Q-loop, making contact
with the gamma phosphate of the ATP molecule. ATP hydrolysis leads to a
conformational change that could facilitate ADP release. In the dimer the two
ABC cassettes contact each other through hydrophobic interactions at the
antiparallel beta-sheet of armI by a two-fold axis
[4][5][3].
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).
In prokaryotes:
Active import transport system components:
- Carbohydrate uptake transporter.
- Cobalt uptake transporter (cbiO).
- Ferric iron uptake transporter.
- Hydrophobic amino acid uptake transporter.
- Iron Chelate uptake transporter.
- Manganese/Zinc/Iron chelate uptake transporter.
- Molybdate uptake transporter.
- Nitrate/Nitrite/Cyanate uptake transporter.
- Peptide/Opine/Nickel uptake transporter.
- Phosphate uptake transporter.
- Phosphonate uptake transporter.
- Polyamine/Opine/Phosphonate uptake transporter.
- Quaternary amine uptake transporter.
- Sulfate uptake transporter.
- Taurine uptake tranporter (tauB).
- Thiamin uptake transporter (thiamin/thiamin pyrophosphate) (thiQ/yabJ).
- Vitamine B12 uptake tranporter (btuD).
Active export transport system components:
- Capsular polysaccharide exporter (kpsT).
- Drug exporter-1: daunorubicin/doxorubicin (drrA); oleandomycin (oleC4).
- Drug resistance ATPase-1.
- Drug/siderophore exporter-3.
- Glucan exporter: Beta-(1,2)-glucan export (chvA/ndvA).
- Lipid A exporter (msbA).
- Lantibiotic exporter: hemolysin/bacteriocin (cylB).
- Lipooligosaccharide exporter (nodulation protein nodI from Rhizobium).
- Lipopolysaccharide exporter (rbfA).
- Micrococin B17 exporter (mcbF).
- Micrococin J25 exporter (mcjD).
- Peptide-2 exporter: competence factor (comA/comB).
- Peptide-3 exporter: modified cyclic peptide (syrD.
- Protein-1 exporter: hemolysin (hlyB).
- Protein-2 exporter: colicin V(cvaB).
- S-layer protein exporter (rsaD/sapD).
- Techoic Acid Exporter (tagH).
In eukaryotes:
- 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.
As a signature pattern for this class of proteins, we use a conserved region
which is located between the 'A' and the 'B' motifs of the ATP-binding site.
The profile we developed is directed against the conserved ABC module by
covering the region between beta strand 1 and alpha helix 9, including not
only the conserved motifs but also structural elements found N and C terminal
to them. Our profile also recognizes the UvrA family which is evolutionarily
related to the ABC transporter family.