The LysE Superfamily of Transport Proteins Involved in Cell Physiology and Pathogenesis.

The LysE superfamily consists of transmembrane transport proteins that catalyze export of amino acids, lipids and heavy metal ions. Statistical means were used to show that it includes newly identified families including transporters specific for (1) tellurium, (2) iron/lead, (3) manganese, (4) calcium, (5) nickel/cobalt, (6) amino acids, and (7) peptidoglycolipids as well as (8) one family of transmembrane electron carriers. Internal repeats and conserved motifs were identified, and multiple alignments, phylogenetic trees and average hydropathy, amphipathicity and similarity plots provided evidence that all members of the superfamily derived from a single common 3-TMS precursor peptide via intragenic duplication. Their common origin implies that they share common structural, mechanistic and functional attributes. The transporters of this superfamily play important roles in ionic homeostasis, cell envelope assembly, and protection from excessive cytoplasmic heavy metal/metabolite concentrations. They thus influence the physiology and pathogenesis of numerous microbes, being potential targets of drug action

Schematic diagrams depicting motifs and highly conserved residues within and between the RhtB (RB) and TerC (TC) families.

<p>A) Schematic diagram of RhtB proteins. B) Schematic diagram of TerC proteins. C) Graphical representation of the shared motifs depicted in Part A and Part B. D) Symbol Legend.</p

Combined AveHAS plot of proteins in the eleven recognized families in the LysE superfamily.

<p>Upper plot: The dark line shows average hydropathy while the light line shows average amphipathicity. Lower plot: The dotted line presents average similarity while the vertical lines indicate average hydropathy, determined by a second method. Numbers above the six bars indicate their TMSs in the basic transport protein unit.</p

Comparison scores between LysE superfamily members.

<p>Scores equal to or greater than 13.0 Standard Deviations (S.D.) are bolded. The number of aligned TMSs is included below each score. Comparisons with the negative control, the Mitochondrial Carrier (MC) family, are provided to the right of the bolded border.</p

Phylogenetic Tree of the LysE Superfamily.

<p>The tree was generated using the SuperFamilyTree program and viewed using FigTree. It depicts the evolutionary relationship between the 11 different families in this study. Clustering indicates closer phylogenetic relationships. The tree is based on tens of thousands of BLAST bit scores generated with the SFT1 program where every protein was compared with every other protein included in the analysis. The SFT2 program was used to integrate all of the information to show the relationships of the eleven families to each other. Associated bootstrap values can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137184#pone.0137184.s029" target="_blank">S29 Fig</a>. When using BLAST bit score comparisons for determining phylogeny, the bootstrap values become less indicative of the reliability and accuracy of observed clustering patterns for very closely related proteins [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137184#pone.0137184.ref019" target="_blank">19</a>].</p

Protein families with Identified Motifs using MEME/MAST.

<p>Protein families demonstrating shared, conserved residues are shown below. HMMTOP was used to predict the TMS location for each motif. Schematic diagrams showing the motif locations and other highly conserved residues are found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137184#pone.0137184.g003" target="_blank">Fig 3A–3G</a>.</p

Proposed evolutionary history for the appearance of the eleven recognized families in the LysE superfamily.

<p>Protein topologies are indicated with bars representing TMSs and numbers indicating the positions of the TMSs in the proposed TMS primordial protein (in parentheses). Families are indicated by their standard abbreviations while numbers indicate "extra" TMSs outside of their basic 6-TMS unit, resulting from intragenic duplication of the primordial 3TMS precursor. A family abbreviation with a particular topology indicates that at least some members of the family are believed to have this topology.</p