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

Abstract

Multidrug resistance (MDR) presents a growing challenge to global public health. Drug extrusion transporters play a critical part in MDR; thus, their mechanisms of substrate recognition are being studied in great detail. In this work, we review common structural features of key transporters involved in MDR. Based on our membrane potential-driving hypothesis, we propose a general energy-coupling mechanism for secondary-active antiporters. This putative mechanism provides a common framework for understanding poly-specificity of most-if not all-MDR transporters.

Interplay between the electrostatic membrane potential and conformational changes in membrane proteins

“…For instance, all PMF‐driven, multidrug resistance, secondary active exporters are hypothesized to utilize the same ΔΨ‐driving mechanism (Fig. ), including those from the MFS family, multidrug and toxin extrusion (MATE) family, small multidrug resistance (SMR) family, and resistance nodulation‐cell division (RND)/AcrB family . Moreover, as an example of multi‐states MPs, the PMF‐driven, F 1 –F O type of ATP synthase possesses two half‐channels connecting to opposite sides of the membrane .…”

P-type ATPases use a domain-association mechanism to couple ATP hydrolysis to conformational change

“…In certain P-ATPases, an additional short amphipathic helix exists at the lumenal end of M9 (Toyoshima et al 2004). Similar amphipathic helices have been found in several major families of membrane proteins, including secondary active transporters, The mechanism of P-type ATPases coupling ATP hydrolysis ATP-binding cassette (ABC) exporters (Zhang et al 2018a), G-protein coupled receptors (GPCRs) (Zhang et al 2014), and voltage-gated ion channels (VGICs) (Zhang et al 2018b). Similar to the Trp and basic residues near the membrane surface, these amphipathic helices are likely to play important roles in restricting the mode of conformational changes of their connected TM-helix termini to sliding-only on the membrane surface (Zhang and Li 2019).…”

“…The phosphorylation and dephosphorylation reactions can be considered as the two key events to drive the conformational cycle of the P-ATPase. Conceptually, they resemble the protonation and deprotonation events in proton motive force (PMF)-driven secondary transporters (Zhang et al 2018a). In other words, the P-ATPase would keep cycling along the path of E 1 ?…”

“…A common function of the members from this family is to convert energy derived from ATP hydrolysis into electrochemical potential by transporting cations across plasma membranes or sequestrating them into membranecompartmented organelles. In turn, generating and maintaining such cross-membrane electrochemical potentials are pivotal to many cellular processes, including operations of secondary active transporters (Zhang et al 2018a) and the cellular signaling system comprising numerous types of ion channels (Zhang et al 2018b). In short, P-ATPases are a ubiquitous, highly conserved, and probably ancient family of transporters that includes many members essential to their corresponding organisms.…”

Dissection of protonation sites for antibacterial recognition and transport in QacA, a multi-drug efflux transporter

“…Antiporters require the protonation of at least one acidic residue to allow substrate binding and consequent H + -release, in the opposite direction to substrate flow [27]. However, it is frequently observed in transporters like LmrP [12], VMATs [28] and BbMAT [16], that more than one acidic residues exist within the transporter vestibule that can exchange two or more protons for every substrate molecule, rendering the process electrogenic [29].…”