Structure and Mechanism of Microbial Membrane Active Transporters

The microbial cytoplasmic membrane functions as a fluidic barrier that regulates the influx and efflux of ions, solutes, metal complexes, and organic compounds into and out of the cell. Microorganisms produce membrane transport proteins that facilitate both the acquisition and extrusion of small molecules. Passive transporters are channels in one form or another, that uptake solutes or other substrates by mass action, ‘down’ their concentration gradients, without consuming energy. The alternative, active transporters, that are the focus of this research topic, drive ‘uphill’ movement of ligands or substrates against their concentration gradients, using energy harvested from light- or chemical-dependent processes, as mediated by proton-motive force or ATP hydrolysis. Besides cytoplasmic membrane active transporters, Gram-negative bacteria contain outer membrane proteins that also conduct active transport (e.g., TonB-dependent receptors for metal complexes). The large group of membrane active transport proteins is diverse in structure, mechanisms and substrate specificities. They are fundamentally important in microbial physiology because they import nutrients, vitamins and metabolites, as well as export waste and toxic substances. They create and maintain ion gradients that act in cellular bioenergetics or homeostasis. Such transporters may constitute virulence factors in bacterial pathogens, and bacteriophage and toxins parasitize them, which provides opportunities to use them as drug targets, or as portals for the uptake of medically relevant molecules.

The availability of high-resolution 3D structures, biophysical data and in silico simulations greatly advances our understanding of microbial active transporters. Yet, many critical, especially mechanistic questions remain unanswered. For example, although over one hundred structures of transporters in the Major Facilitator Superfamily are now solved, the mechanism of ion-coupling in electrochemical force is not fully understood. The same mechanistic gap exists for TonB-dependent transport systems, regarding the energy transduction from the energized bacterial cytoplasmic membrane to the unenergized outer membrane. Active transporters are dynamic proteins that adopt multiple conformational states and may undergo induced fit during translocation of their substrates, but structural data often only provides snapshots within their transport cycles. Thus, besides structures obtained in vitro, new in vivo and in silico analyses will further elucidate protein dynamics in active transport processes. In this collection of articles we expect to deliver novel insights into the mechanisms and structure-function relationships of microbial active transporters, from new structures, biochemical and biophysical results, and computer simulations.

The transporters of interest include bacteriorhodopsins, ATPase pumps, ABC transporters, MFS transporters, efflux pumps, TonB-dependent transporters and TRAP transporters in archaea, bacteria, and fungi. A few examples of microbial active transporter-related topics include:

• Membrane protein structure
• Transport mechanisms
• Structure-function relationships
• Molecular dynamics simulations
• Lipid-transporter interactions
• Interactions with inhibitors and drugs
• New experimental tools and methods