Abstract:
ATP-binding cassette (ABC) transporters are membrane-bound
molecular pumps that form one of the largest of all protein
families. Several of them are central to phenomena of biomedical
interest, including cystic fibrosis and resistance to chemotherapeutic
drugs. ABC transporters share a common architecture comprising
two hydrophilic nucleotide-binding domains (NBDs) and two
hydrophobic transmembrane domains (TMDs) that form the substrate
pathway across the membrane. The conformational changes
in the NBDs induced by ATP hydrolysis and the means by which
they are transmitted to the TMDs to effect substrate translocation
remain largely unknown. We have performed a molecular dynams
simulation of HisP, the well studied NBD of the bacterial
nistidine permease, to identify hinges and switches of the NBD
conformational transitions and subunit-subunit interfaces. This
analysis reveals that the TMDs regulate ATP hydrolysis by controlling
conformational transitions of the NBD helical domains, and
identifies the conformational changes and the crucial TMD:NBD
interface, by which the energy of ATP hydrolysis is transmitted to
the TMDs. We also define the conformational transitions of the
Q-Ioop, a key element of the NBD mechanism, and identify pathways
by which Q-Ioop switching is coordinated with TMD and NBD
conformational changes. We propose a model for the catalytic
cycle of ABC transporters that shows how substrate-binding and
transport by the TMDs may be coordinated and coupled with ATP
binding and hydrolysis in the NBDs.
