Energy coupling mechanisms of AcrB-like RND transporters

Abstract

Prokaryotic AcrB-like proteins belong to a family of transporters of the RND superfamily, and as main contributing factor to multidrug resistance pose a tremendous threat to future human health. A unique feature of AcrB transporters is the presence of two separate domains responsible for carrying substrate and generating energy. Significant progress has been made in elucidating the three-dimensional structures of the homo-trimer complexes of AcrB-like transporters, and a three-step functional rotation was identified for this class of transporters. However, the detailed mechanisms for the transduction of the substrate binding signal, as well as the energy coupling processes between the functionally distinct domains remain to be established. Here, we propose a model for the interdomain communication in AcrB that explains how the substrate binding signal from the substrate-carrier domain triggers protonation in the transmembrane domain. Our model further provides a plausible mechanism that explains how protonation induces conformational changes in the substrate-carrier domain. We summarize the thermodynamic principles that govern the functional cycle of the AcrB trimer complex.Electronic supplementary materialThe online version of this article (doi:10.1007/s41048-017-0042-y) contains supplementary material, which is available to authorized users.

Thermodynamic secrets of multidrug resistance: A new take on transport mechanisms of secondary active antiporters

“…This differential binding (i.e. Δ G D (S) > 0) in the porter domain is driven by the PMF energy transduced from the TM domain …”

“…During a transport cycle, energetically favorable substrate binding and release trigger local conformational changes in the porter domain by reorganizing its subdomains . These binding signals are transduced from the porter layer to the TM layer presumably through two conserved double‐strand β‐sheets, and result in a 13° relative rotations between TMs 4 and 10 in the TM domain . More specifically, during protonation the positively changed sidechain of K940 TM10 moves away from D407 TM4 .…”

“…In contrast, during deprotonation K940 TM10 moves back between sidechains of D407 TM4 and D408 TM4 . Furthermore, analogously to the key residues of other PMF‐driven two‐state transporters, in its protonation state D407 TM4 is connected to the periplasmic side via a proton wire; and in the deprotonated state D407 TM4 switches to another proton wire connecting to the cytosolic side . Together, these micro‐environmental changes of D407 TM4 result in alternation of its protonation status, which in turn generates electrostatic forces that drive conformational cycling in the porter layer.…”

“…One characteristic of the RND family is the structural separation of the substrate‐transport domain from that utilizing PMF. Thus, the function of an RND transporter depends on proper communication between the two parts . This signaling path serves as an additional target for blocking transport activity in RND transporters.…”

“…Five major families of exporters have been found to be involved in MDR (Fig. ), namely the major facilitator superfamily (MFS), multidrug and toxin extrusion (MATE) family, small multidrug resistance (SMR) family, resistance nodulation‐cell division (RND) family, and ATP‐binding cassette (ABC) transporters . While these transporters share common functions in MDR, their physiological roles are vastly diverse .…”