Functional Roles of the Conserved Amino Acid Sequence Motif C, the Antiporter Motif, in Membrane Transporters of the Major Facilitator Superfamily

SIMPLE SUMMARY: A phospholipid membrane covers all living cells, forming an impenetrable barrier circumvented by solute transporters in the cell membrane. These proteins comprise energy-requiring systems, called active transporters, and those not requiring energy, called passive transporters. The major facilitator superfamily harbors thousands of transport proteins found in all living organisms, from bacteria to humans. Alignments of multiple amino acid sequences uncovered highly conserved sequence motifs are known to play important functional roles. One of these conserved sequences, the antiporter sequence motif or motif C, participates in the molecular mechanism of antimicrobial efflux in cancer cells and bacterial pathogens. The biological implications of the antiporter motif’s functional roles and usefulness are considered here. ABSTRACT: The biological membrane surrounding all living cells forms a hydrophobic barrier to the passage of biologically important molecules. Integral membrane proteins called transporters circumvent the cellular barrier and transport molecules across the cell membrane. These molecular transporters enable the uptake and exit of molecules for cell growth and homeostasis. One important collection of related transporters is the major facilitator superfamily (MFS). This large group of proteins harbors passive and secondary active transporters. The transporters of the MFS consist of uniporters, symporters, and antiporters, which share similarities in structures, predicted mechanism of transport, and highly conserved amino acid sequence motifs. In particular, the antiporter motif, called motif C, is found primarily in antiporters of the MFS. The antiporter motif’s molecular elements mediate conformational changes and other molecular physiological roles during substrate transport across the membrane. This review article traces the history of the antiporter motif. It summarizes the physiological evidence reported that supports these biological roles.