title: A study of the evolution of inverted-topology repeats from LeuT-fold transporters using AlignMe.
abstract: X-ray crystal structures have revealed that numerous secondary transporter proteins originally categorized into different sequence families share similar structures, namely, the LeuT fold. The core of this fold consists of two units of five transmembrane helices, whose conformations have been proposed to exchange to form the two alternate states required for transport. That these two units are related implies that LeuT-like transporters evolved from gene-duplication and fusion events. Thus, the origins of this structural repeat may be relevant to the evolution of transport function. However, the lack of significant sequence similarity requires sensitive sequence search methods for analyzing their evolution. To this end, we developed a software application called AlignMe, which can use various types of input information, such as residue hydrophobicity, to perform pairwise alignments of sequences and/or of hydropathy profiles of (membrane) proteins. We used AlignMe to analyze the evolutionary relationships between repeats of the LeuT fold. In addition, we identified proteins from the so-called DedA family that potentially share a common ancestor with these repeats. DedA domains have been implicated in, e.g., selenite uptake; they are found widely distributed across all kingdoms of life; two or more DedA domains are typically found per genome, and some may adopt dual topologies. These results suggest that DedA proteins existed in ancient organisms and may function as dimers, as required for a would-be ancestor of the LeuT fold. In conclusion, we provide novel insights into the evolution of this important structural motif and thus potentially into the alternating-access mechanism of transport itself.
authors.affiliation: Computational Structural Biology Group, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany.
authors.forename: Kamil
authors.initials: K
authors.lastname: Khafizov
authors.forename: René
authors.initials: R
authors.lastname: Staritzbichler
authors.forename: Marcus
authors.initials: M
authors.lastname: Stamm
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Forrest
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D026901:Membrane Transport Proteins / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012984:Software
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins