New Insights into the Evolution and Gene Structure of the Mitochondrial Carrier Family Unveiled by Analyzing the Frequent and Conserved Intron Positions

Abstract

Mitochondrial carriers (MCs) belong to a eukaryotic protein family of transporters that in higher organisms is called the solute carrier family 25 (SLC25). All MCs have characteristic triplicated sequence repeats forming a threefold-symmetrical structure of a six-transmembrane α-helix bundle with a centrally-located substrate binding site. Biochemical characterization has shown that MCs altogether transport a wide variety of substrates but can be divided into subfamilies, each transporting a few specific substrates. We have investigated the intron positions in the human MC genes and their orthologs of highly diversified organisms. The results demonstrate that several intron positions are present in numerous MC sequences at the same specific points, of which some are three-fold symmetry related. Many of these frequent intron positions are also conserved in subfamilies or in groups of subfamilies transporting similar substrates. The analyses of the frequent and conserved intron positions in MCs suggest phylogenetic relationships not only between close but also distant homologs as well as a possible involvement of the intron positions in the evolution of the substrate specificity diversification of the MC family members.

Phylogenetic Analysis Guides Transporter Protein Deorphanization: A Case Study of the SLC25 Family of Mitochondrial Metabolite Transporters

“…While several phylogenetic analyses have been performed on automatically collected SLC25 sequences across a broad range of eukaryotic taxa [ 65 , 66 , 67 ], our analysis, which focused on a few model organisms, provides unique insights to guide future functional annotation. Because the model organism proteomes are well curated, we were able to carefully exhaust all SLC25s in each species and more importantly, immediately distinguish the evolutionarily conserved SLC25s from the SLC25s that might be due to recent innovation in vertebrates or in mammals.…”

“…A phylogenetic analysis could potentially guide experimental ligand characterization efforts for certain SLC25 transporters as an orthologous strategy to in vitro proteoliposome-based transport assays, cell-based assays and in vivo studies. Other molecular evolution approaches could also provide exciting insights [ 66 ]. A comprehensive evaluation of how a homology search and phylogenetic analysis could guide deorphanization efforts probably requires a “dream world” scenario in which experimentally validated functional annotation is available for every C luster of O rthologous G roup (COG) in bacteria and in eukaryotes [ 75 ].…”