What Can a Living Fossil Tell Us About Evolution and Mechanism of Ion-Coupled Transporters: The Story of Small Multidrug Transporters

Abstract

Small Multidrug Resistance (SMR) transporters are small homo- or hetero-dimers that confer resistance to multiple toxic compounds by exchanging substrate with protons. They reside in the inner membrane of bacteria and in halophilic and methanogenic archaea and because many of their substrates are routinely used as antibiotics and antiseptics, they have been associated with the phenomenon of multidrug resistance. EmrE, the most studied SMR member, has presented biochemists with unusual surprises regarding its topology and raised an interesting controversy since structural information was in an apparent conflict with biochemical data. One of the reasons for the controversy was the assumption that, to ensure proper function, membrane proteins must be inserted by a mechanism that warrants a unique topology. As it turns out, EmrE and other SMR transporters display a remarkable plasticity regarding topology in the membrane, interaction between subunits, and interaction with substrates. This plasticity implies a high evolvability of these proteins and, as a consequence, a lack of commitment that facilitates acquisition of new functions and topologies. Because of this high evolvability, we suggest that SMRs are living fossils at an evolutionary junction. Study of their properties provides a wonderful glimpse at the evolution and mechanism of ion-coupled transporters.