Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae

<p>Abstract</p> <p>Background</p> <p>The drug/metabolite transporter superfamily comprises a diversity of protein domain families with multiple functions including transport of nucleotide sugars. Drug/metabolite transporter domains are contained in both solute carrier families 30, 35 and 39 proteins as well as in acyl-malonyl condensing enzyme proteins. In this paper, we present an evolutionary analysis of nucleotide sugar transporters in relation to the entire superfamily of drug/metabolite transporters that considers crucial intra-protein duplication events that have shaped the transporters. We use a method that combines the strengths of hidden Markov models and maximum likelihood to find relationships between drug/metabolite transporter families, and branches within families.</p> <p>Results</p> <p>We present evidence that the triose-phosphate transporters, domain unknown function 914, uracil-diphosphate glucose-N-acetylglucosamine, and nucleotide sugar transporter families have evolved from a domain duplication event before the radiation of <it>Viridiplantae </it>in the EamA family (previously called domain unknown function 6). We identify previously unknown branches in the solute carrier 30, 35 and 39 protein families that emerged simultaneously as key physiological developments after the radiation of <it>Viridiplantae</it>, including the "35C/E" branch of EamA, which formed in the lineage of <it>T. adhaerens </it>(<it>Animalia</it>). We identify a second cluster of DMTs, called the domain unknown function 1632 cluster, which has non-cytosolic N- and C-termini, and thus appears to have been formed from a different domain duplication event. We identify a previously uncharacterized motif, G-X(6)-G, which is overrepresented in the fifth transmembrane helix of C-terminal domains. We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought.</p> <p>Conclusions</p> <p>The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before <it>Viridiplantae</it>, showing for the first time the significance of EamA.</p

Insulin receptor-like ectodomain genes and splice variants are found in both arthropods and human brain cDNA

Truncated receptor ectodomains have been described for several classes of cell surface receptors, including those that bind to growth factors, cytokines, immunoglobulins, and adhesion molecules. Soluble receptor isoforms are typically generated by proteolytic cleavage of the cell surface receptor or by alternative splicing of RNA transcripts arising from the same gene encoding the full-length receptor. Both the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR) families produce soluble receptor splice variants in vertebrates and truncated forms of insulin receptor-like sequences have previously been described in Drosophila. The EGFR and INSR ectodomains share significant sequence homology with each other suggestive of a common evolutionary origin. We discovered novel truncated insulin receptor-like variants in several arthropod species. We performed a phylogenetic analysis of the conserved extracellular receptor L1 and L2 subdomains in invertebrate species. While the segregation of insulin receptor-like L1 and L2 domains indicated that an internal domain duplication had occurred only once, the generation of truncated insulin receptor-like sequences has occurred multiple times. The significance of this work is the previously unknown and widespread occurrence of truncated isoforms in arthropods, signifying that these isoforms play an important functional role, potentially related to such isoforms in mammals

Bioinformatic analyses of integral membrane transport proteins encoded within the genome of the planctomycetes species, Rhodopirellula baltica

Rhodopirellula baltica (R. baltica) is a Planctomycete, known to have intracellular membranes. Because of its unusual cell structure and ecological significance, we have conducted comprehensive analyses of its transmembrane transport proteins. The complete proteome of R. baltica was screened against the Transporter Classification Database (TCDB) to identify recognizable integral membrane transport proteins. 342 proteins were identified with a high degree of confidence, and these fell into several different classes. R. baltica encodes in its genome channels (12%), secondary carriers (33%), and primary active transport proteins (41%) in addition to classes represented in smaller numbers. Relative to most non-marine bacteria, R. baltica possesses a larger number of sodium-dependent symporters but fewer proton-dependent symporters, and it has dimethylsulfoxide (DMSO) and trimethyl-amine-oxide (TMAO) reductases, consistent with its Na-rich marine environment. R. baltica also possesses a Na-translocating NADH:quinone dehydrogenase (Na-NDH), a Na efflux decarboxylase, two Na-exporting ABC pumps, two Na-translocating F-type ATPases, two Na:H antiporters and two K:H antiporters. Flagellar motility probably depends on the sodium electrochemical gradient. Surprisingly, R. baltica also has a complete set of H-translocating electron transport complexes similar to those present in α-proteobacteria and eukaryotic mitochondria. The transport proteins identified proved to be typical of the bacterial domain with little or no indication of the presence of eukaryotic-type transporters. However, novel functionally uncharacterized multispanning membrane proteins were identified, some of which are found only in Rhodopirellula species, but others of which are widely distributed in bacteria. The analyses lead to predictions regarding the physiology, ecology and evolution of R. baltica

Evolution of Membrane Bound Proteins and their Ligands : The Melanocortin (MC) Receptor Inverse Agonists AgRP2, ASIP2, Drug/Metabolite Transporters, and SPNS1

Integral membrane proteins play a key role hormonal and neuronal signaling. Transmembrane helix (TM) proteins form about 27% of the human proteome. Furthermore, 44% of the human drug targets are receptors, and 19% of these are seven-transmembrane domain receptors (GPCRs), which constitute 4% of the entire protein-coding genome. After receptors, solute carriers (SLCs) constitute the second largest superfamily of TM proteins. Three of the largest SLC families contain protein domains that are members of the drug/metabolite transporter clan. We present evidence that the drug/metabolite transporter (DMT) families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. We renamed several transporters, and introduced the new HGNC-approved nomenclature of SLC35G1 – 6. We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Holocephali. However, we do not find any of these genes in lamprey or lancelet, suggesting that the MCA and MCB receptors function without antagonists in lamprey. We report that a venom peptide in Plectreurys tristis has the same cysteine knot structure as fish AgRP2, a higher similarity than previously known. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is likely to be the most ancestral, first splitting from a common ancestor to ASIP and A2. We introduce a new technique for synteny detection, sinusoidal Hough transform. We found that the known obesity SNPs in SH2B1, rs4788102 (p=0.0023) and rs7498665 (p=0.0018) were associated with triglyceride levels in the North Swedish Population Health Study (NSPHS) cohort, consisting of 719 individuals from the Karesuando parish in northern Sweden. To account for kinship, the SH2B1 SNPs, and four SNPs in the expanded region were analyzed for association with triglyceride levels using SOLAR. We found a stronger signal (p=0.0009) for a SNP, near SH2B1, rs8045689, located in an intron of SPNS1 which is structurally similar to a sphingolipid transporter

Evolution of Membrane Bound Proteins and their Ligands : The Melanocortin (MC) Receptor Inverse Agonists AgRP2, ASIP2, Drug/Metabolite Transporters, and SPNS1

Integral membrane proteins play a key role hormonal and neuronal signaling. Transmembrane helix (TM) proteins form about 27% of the human proteome. Furthermore, 44% of the human drug targets are receptors, and 19% of these are seven-transmembrane domain receptors (GPCRs), which constitute 4% of the entire protein-coding genome. After receptors, solute carriers (SLCs) constitute the second largest superfamily of TM proteins. Three of the largest SLC families contain protein domains that are members of the drug/metabolite transporter clan. We present evidence that the drug/metabolite transporter (DMT) families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. We renamed several transporters, and introduced the new HGNC-approved nomenclature of SLC35G1 – 6. We show the presence of AgRP and ASIP in elephant shark, a cartilaginous fish belonging to the subclass of Holocephali. However, we do not find any of these genes in lamprey or lancelet, suggesting that the MCA and MCB receptors function without antagonists in lamprey. We report that a venom peptide in Plectreurys tristis has the same cysteine knot structure as fish AgRP2, a higher similarity than previously known. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is likely to be the most ancestral, first splitting from a common ancestor to ASIP and A2. We introduce a new technique for synteny detection, sinusoidal Hough transform. We found that the known obesity SNPs in SH2B1, rs4788102 (p=0.0023) and rs7498665 (p=0.0018) were associated with triglyceride levels in the North Swedish Population Health Study (NSPHS) cohort, consisting of 719 individuals from the Karesuando parish in northern Sweden. To account for kinship, the SH2B1 SNPs, and four SNPs in the expanded region were analyzed for association with triglyceride levels using SOLAR. We found a stronger signal (p=0.0009) for a SNP, near SH2B1, rs8045689, located in an intron of SPNS1 which is structurally similar to a sphingolipid transporter