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

Västermark Å, Almén MS, Simmen MW, Fredriksson R, Schiöth HB - BMC Evol. Biol. (2011)

Bottom Line: 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.The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Box 593, 751 24, Uppsala, Sweden. ake.vastermark@neuro.uu.se

ABSTRACT

Background: 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.

Results: 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 Viridiplantae 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 Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). 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.

Conclusions: The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.

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Figure showing TM structure in relation to overlaid DLP-SVM prediction. The figure shows TMHMM transmembrane predictions and DLP-SVM predictions for example sequences representing human asymmetric DMT families: NIPA1 (DUF803), SLC30A1 (Cation efflux), SLC39A1 (Zip). TMHMM (http://www.cbs.dtu.dk/services/TMHMM/) is used with default settings, and DLP-SVM is used with the settings presented in the methods section. The SVM peak values and SVM scales, projected on the TMHMM figure using a bold blue curve are as follows: 1.159 (-3 => 1.5), 2.287 (-3 => 3), 1.941 (-2.5 => 2.5). The presumed respective two domain structure is 4+5, 4+2, 3+5 TM (the red peaks represent TM helices).
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Figure 1: Figure showing TM structure in relation to overlaid DLP-SVM prediction. The figure shows TMHMM transmembrane predictions and DLP-SVM predictions for example sequences representing human asymmetric DMT families: NIPA1 (DUF803), SLC30A1 (Cation efflux), SLC39A1 (Zip). TMHMM (http://www.cbs.dtu.dk/services/TMHMM/) is used with default settings, and DLP-SVM is used with the settings presented in the methods section. The SVM peak values and SVM scales, projected on the TMHMM figure using a bold blue curve are as follows: 1.159 (-3 => 1.5), 2.287 (-3 => 3), 1.941 (-2.5 => 2.5). The presumed respective two domain structure is 4+5, 4+2, 3+5 TM (the red peaks represent TM helices).

Mentions: Canonical example sequences of these anomalous ('asymmetric') families were analyzed with DLP-SVM (an SVM that recognizes domain linker peptides) and TMHMM [Figure 1], suggesting a 4 + 5, 4 + 2, and 3 + 5 TM architecture in relation to the DMT domain border, respectively. Finally, placement of the domain boundary in the Zip and Cation efflux families was determined by the concurrent location of Pfam low complexity regions as well as a large gapped region in the alignment, and in the case of DUF803 by use of a generic HMM recognizing the DMT-1 and DMT-2 domains. Tables S4 [additional file 5: supplementary table S4] and 2 list different evidence type used to locate domain border and the final conclusion for each family.


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

Västermark Å, Almén MS, Simmen MW, Fredriksson R, Schiöth HB - BMC Evol. Biol. (2011)

Figure showing TM structure in relation to overlaid DLP-SVM prediction. The figure shows TMHMM transmembrane predictions and DLP-SVM predictions for example sequences representing human asymmetric DMT families: NIPA1 (DUF803), SLC30A1 (Cation efflux), SLC39A1 (Zip). TMHMM (http://www.cbs.dtu.dk/services/TMHMM/) is used with default settings, and DLP-SVM is used with the settings presented in the methods section. The SVM peak values and SVM scales, projected on the TMHMM figure using a bold blue curve are as follows: 1.159 (-3 => 1.5), 2.287 (-3 => 3), 1.941 (-2.5 => 2.5). The presumed respective two domain structure is 4+5, 4+2, 3+5 TM (the red peaks represent TM helices).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3111387&req=5

Figure 1: Figure showing TM structure in relation to overlaid DLP-SVM prediction. The figure shows TMHMM transmembrane predictions and DLP-SVM predictions for example sequences representing human asymmetric DMT families: NIPA1 (DUF803), SLC30A1 (Cation efflux), SLC39A1 (Zip). TMHMM (http://www.cbs.dtu.dk/services/TMHMM/) is used with default settings, and DLP-SVM is used with the settings presented in the methods section. The SVM peak values and SVM scales, projected on the TMHMM figure using a bold blue curve are as follows: 1.159 (-3 => 1.5), 2.287 (-3 => 3), 1.941 (-2.5 => 2.5). The presumed respective two domain structure is 4+5, 4+2, 3+5 TM (the red peaks represent TM helices).
Mentions: Canonical example sequences of these anomalous ('asymmetric') families were analyzed with DLP-SVM (an SVM that recognizes domain linker peptides) and TMHMM [Figure 1], suggesting a 4 + 5, 4 + 2, and 3 + 5 TM architecture in relation to the DMT domain border, respectively. Finally, placement of the domain boundary in the Zip and Cation efflux families was determined by the concurrent location of Pfam low complexity regions as well as a large gapped region in the alignment, and in the case of DUF803 by use of a generic HMM recognizing the DMT-1 and DMT-2 domains. Tables S4 [additional file 5: supplementary table S4] and 2 list different evidence type used to locate domain border and the final conclusion for each family.

Bottom Line: 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.The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Box 593, 751 24, Uppsala, Sweden. ake.vastermark@neuro.uu.se

ABSTRACT

Background: 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.

Results: 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 Viridiplantae 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 Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). 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.

Conclusions: The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.

Show MeSH