ABC transporter ModBC in complex with its binding protein ModA
Archaeoglobus fulgidus (archaea, thermophile)
ATP-binding cassette (ABC) transporters are proteins that utilize the energy of ATP hydrolysis to transport various substrates across cell membranes, and are present in various organisms. There are many types of ABC transporters which work in defence such as alien substance excretion or transporter associated with antigen processing (TAP), cause multidrug resistance (MDR) of cancer cells, and so on. Some mutations may also cause hereditary diseases such as cystic fibrosis, lymphopenia, adrenoleukodystrophy, and revealing how to inhibit protein activity may be valuable to develop therapeutic drug. In eukaryote the main role of it is to export molecules, whereas in bacteria, the main role is to import nutrients such as sugars, vitamins, and metal ions, including rare elements such as molybdenum.
Here we present the 3.1 angstrom crystal structure of a putative molybdate transporter (ModB2C2) from Archaeoglobus fulgidus in complex with its binding protein (ModA). ABC transporters consist of two transmembrane domains (TMDs) that provide a translocation pathway, and two cytoplasmic nucleotide-binding domains (NBDs) that hydrolyse ATP and drive the transport reaction. Twelve transmembrane helices of the two ModB subunits, consisting TMD domain (see Fig.1), provide an inward-facing conformation, with a closed gate near the external membrane boundary (see Fig.2, 3). The gate region which opens and closes the gate is highly conserved among molybdate importers.
Two ModC comprising the NBD domain hydrolyses ATP. Binding of ATP to the cleft of the upper central site of NBD causes a conformational change in NBD. In Fig. 4, there are two ATP binding sites in front and behind, though cannot be seen. It suggests two ATP will be consumed during each transport. This ATP binding site is called the P-loop and consists of the LSGGQ motif, which is highly conserved in various ATP hydrolysis (ATPase) proteins. This LSGGQ motif contacts with the short cytoplasmic helix (4a) of ModB subunit. This ModC-ModB interface transmits conformational changes, causes ModB changes from inward-facing conformation to outward-facing conformation, and importing tungstate into the cell. A hook-like structure is observed in the carboxy termini of each ModC (in the bottom area of Fig.4), and this structure keeps them linked while the substitute transportation.
ModA captures the substance (tungstate) for importing into the cell, provides it to the outer side of the transporter. Coordination of tungstate to ModA causes conformational change at the interface between ModB, and open gate. Five subunits, one ModA , two ModB (TMD), and two ModC (NBD), comprise this ABC transporter, although the structure of two ABC transporters, facing each ModA, is shown in this entry.
Protein Data Bank (PDB)
author: Takahiro Kudou