Abstract
Key points: Small transmembrane proteins such as FXYDs, which interact with Na+,K+-ATPase, and the micropeptides that interact with sarco/endoplasmic reticulum Ca2+-ATPase play fundamental roles in regulation of ion transport in vertebrates. Uncertain evolutionary origins and phylogenetic relationships among these regulators of ion transport have led to inconsistencies in their classification across vertebrate species, thus hampering comparative studies of their functions. We discovered the first FXYD homologue in sea lamprey, a basal jawless vertebrate, which suggests small transmembrane regulators of ion transport emerged early in the vertebrate lineage. We also identified 13 gene subfamilies of FXYDs and propose a revised, phylogeny-based FXYD classification that is consistent across vertebrate species. These findings provide an improved framework for investigating physiological and pathophysiological functions of small transmembrane regulators of ion transport. Abstract: Small transmembrane proteins are important for regulation of cellular ion transport. The most prominent among these are members of the FXYD family (FXYD1–12), which regulate Na+,K+-ATPase, and phospholamban, sarcolipin, myoregulin and DWORF, which regulate the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). FXYDs and regulators of SERCA are present in fishes, as well as terrestrial vertebrates; however, their evolutionary origins and phylogenetic relationships are obscure, thus hampering comparative physiological studies. Here we discovered that sea lamprey (Petromyzon marinus), a representative of extant jawless vertebrates (Cyclostomata), expresses an FXYD homologue, which strongly suggests that FXYDs predate the emergence of fishes and other jawed vertebrates (Gnathostomata). Using a combination of sequence-based phylogenetic analysis and conservation of local chromosome context, we determined that FXYDs markedly diversified in the lineages leading to cartilaginous fishes (Chondrichthyes) and bony vertebrates (Euteleostomi). Diversification of SERCA regulators was much less extensive, indicating they operate under different evolutionary constraints. Finally, we found that FXYDs in extant vertebrates can be classified into 13 gene subfamilies, which do not always correspond to the established FXYD classification. We therefore propose a revised classification that is based on evolutionary history of FXYDs and that is consistent across vertebrate species. Collectively, our findings provide an improved framework for investigating the function of ion transport in health and disease.
| Original language | English |
|---|---|
| Journal | Journal of Physiology |
| Volume | 595 |
| Issue number | 14 |
| Pages (from-to) | 4611-4630 |
| Number of pages | 20 |
| ISSN | 0022-3751 |
| DOIs | |
| Publication status | Published - 15.07.2017 |
Funding
This study was supported with funding from the Swedish Research Council, Novo Nordisk Research Foundation, and the Strategic Research Programme in Diabetes at Karolinska Institutet. M.K.S. and Y.I.W. are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). S.P. is supported by the Slovenian Research Agency (grants P3-0043, J7-7138, and J3-6794). We thank Drs Marc Gilbert, Dan Larhammar, Alexey Shipunov, Kathleen Sweadner and Lev Yampolsky for productive discussions and critical reading of the manuscript. CDS: coding DNA sequence; part of the genomic DNA that is translated. Clade: a taxon that includes all species descending from a common ancestor. Conserved synteny: synteny means on the same strand, while conserved synteny refers to conservation of gene order on the chromosomes of different, but related, species. ESTs: expressed sequence tags are short reads from the cDNA and represent genes that are expressed in a given tissue and/or developmental stage. Homologues (homologous genes): Genes that originate from a common ancestor. Orthologues (orthologous genes): Genes in different species originating from the same ancestral gene. For instance, FXYD2 is a deeply ancestral FXYD gene, from which all FXYD2 genes in vertebrates are derived. Paralogues (paralogous genes): Genes originating from the duplication of the same ancestral gene. For instance, duplication of FXYD2 in Actinopterygii produced fish-specific paralogue of FXYD2 (FXYD2f).
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
