Abstract
During the evolution of cellular bioenergetics, many protein families have been fashioned to match the availability and replenishment in energy supply. Molecular motors and primary transporters essentially need ATP to function while proteins involved in cell signaling or translation consume GTP. ATP-Binding Cassette (ABC) transporters are one of the largest families of membrane proteins gathering several medically relevant members that are typically powered by ATP hydrolysis. Here, a Streptococcus pneumoniae ABC transporter responsible for fluoroquinolones resistance in clinical settings, PatA/PatB, is shown to challenge this concept. It clearly favors GTP as the energy supply to expel drugs. This preference is correlated to its ability to hydrolyze GTP more efficiently than ATP, as found with PatA/PatB reconstituted in proteoliposomes or nanodiscs. Importantly, the ATP and GTP concentrations are similar in S. pneumoniae supporting the physiological relevance of GTP as the energy source of this bacterial transporter.
Highlights
Chemical energy is required to sustain life since any cellular task such as DNA maintenance or replication, translation, cell signaling or transport is an energy-driven process
The heterodimer PatA/PatB involved in the resistance to fluoroquinolone was shown previously to transport Hoechst 33342 in vitro when inside-out membrane vesicles (IMV) were prepared from E. coli that contained overexpressed PatA/PatB
Apart from the ion-gradient used by families of secondary transporters to exchange molecules across a membrane, the main energy supply used to power the proteins involved in these processes is mostly provided by the hydrolysis of two nucleotides, ATP or GTP
Summary
Chemical energy is required to sustain life since any cellular task such as DNA maintenance or replication, translation, cell signaling or transport is an energy-driven process. Many proteins have been shaped to harness the chemical energy provided by hydrolysis of the β-γ phosphate bond of a nucleotide, mainly ATP or GTP, to mediate their dedicated function[1] They predominantly belong to one of the most ancient protein super-families, the P-loop NTPases[2,3], and their overwhelming presence in all species, between 10 to 18% of each proteome[4], reflects their versatile and pivotal functions in many cellular pathways[5]. These proteins contain two specific motifs in their sequences: the Walker A motif[6], G/AX4GKT/S, involved in the proper positioning of the polyphosphate moiety of ATP/GTP, and the Walker B motif. The multidrug ABC transporter, PatA/PatB, has been shown to be involved in the resistance of S. pneumoniae to fluoroquinolones in clinical settings[22,23] and we have shown that both subunits are required to form a functional heterodimeric multidrug transporter in vitro[24]
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