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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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Multidimensional scaling analysis and distance analysis of EamA-derived nucleotide sugar transporters, first and second domains. Figure 3A: Two-dimensional representation of the similarity relationships between the domains of the nucleotide sugar transporter DMT families with human members, as obtained by non-metric multidimensional scaling. First domains are represented by red circles, second domains by blue triangles. The MDS fit measures (s-stress = 0.08, RSQ = 0.97) indicate that the inter-domain distances in this configuration reflect well the original inter-domain similarity values. Figure 3B: HHsearch all-against-all clustering is done, using a 99.05% probability cutoff, because this was the highest cutoff we could use and still retain a connected graph. The results are organized as a pivot table in Open Office 3 and viewed as a graph in Cytoscape (v2.6.3). The graph is arranged manually to achieve maximum separation between first and second domains, and to achieve no overlapping edges (planarity). The HHsearch values quoted between two DMT domains may fluctuate slightly depending on which domain is used as query; if so, the number presented is the average result.
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Figure 3: Multidimensional scaling analysis and distance analysis of EamA-derived nucleotide sugar transporters, first and second domains. Figure 3A: Two-dimensional representation of the similarity relationships between the domains of the nucleotide sugar transporter DMT families with human members, as obtained by non-metric multidimensional scaling. First domains are represented by red circles, second domains by blue triangles. The MDS fit measures (s-stress = 0.08, RSQ = 0.97) indicate that the inter-domain distances in this configuration reflect well the original inter-domain similarity values. Figure 3B: HHsearch all-against-all clustering is done, using a 99.05% probability cutoff, because this was the highest cutoff we could use and still retain a connected graph. The results are organized as a pivot table in Open Office 3 and viewed as a graph in Cytoscape (v2.6.3). The graph is arranged manually to achieve maximum separation between first and second domains, and to achieve no overlapping edges (planarity). The HHsearch values quoted between two DMT domains may fluctuate slightly depending on which domain is used as query; if so, the number presented is the average result.

Mentions: Non-metric multidimensional scaling [34] was used (see Methods) to construct a two-dimensional representation of the similarity data (Figure 3A) in which the domains are positioned so that the distances between them reflects as much as possible the original dissimilarity values. The resulting configuration shows a striking bipartitioning of the domains that recapitulates whether they are first or second domains. Furthermore, the domains nearest the notional "boundary" between the two clusters are EamA-1 (DUF6-1) and EamA-2 (DUF6-2). Our interpretation of this is that it suggests that EamA was the original family from which the other four nucleotide sugar transporter families evolved.


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)

Multidimensional scaling analysis and distance analysis of EamA-derived nucleotide sugar transporters, first and second domains. Figure 3A: Two-dimensional representation of the similarity relationships between the domains of the nucleotide sugar transporter DMT families with human members, as obtained by non-metric multidimensional scaling. First domains are represented by red circles, second domains by blue triangles. The MDS fit measures (s-stress = 0.08, RSQ = 0.97) indicate that the inter-domain distances in this configuration reflect well the original inter-domain similarity values. Figure 3B: HHsearch all-against-all clustering is done, using a 99.05% probability cutoff, because this was the highest cutoff we could use and still retain a connected graph. The results are organized as a pivot table in Open Office 3 and viewed as a graph in Cytoscape (v2.6.3). The graph is arranged manually to achieve maximum separation between first and second domains, and to achieve no overlapping edges (planarity). The HHsearch values quoted between two DMT domains may fluctuate slightly depending on which domain is used as query; if so, the number presented is the average result.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Multidimensional scaling analysis and distance analysis of EamA-derived nucleotide sugar transporters, first and second domains. Figure 3A: Two-dimensional representation of the similarity relationships between the domains of the nucleotide sugar transporter DMT families with human members, as obtained by non-metric multidimensional scaling. First domains are represented by red circles, second domains by blue triangles. The MDS fit measures (s-stress = 0.08, RSQ = 0.97) indicate that the inter-domain distances in this configuration reflect well the original inter-domain similarity values. Figure 3B: HHsearch all-against-all clustering is done, using a 99.05% probability cutoff, because this was the highest cutoff we could use and still retain a connected graph. The results are organized as a pivot table in Open Office 3 and viewed as a graph in Cytoscape (v2.6.3). The graph is arranged manually to achieve maximum separation between first and second domains, and to achieve no overlapping edges (planarity). The HHsearch values quoted between two DMT domains may fluctuate slightly depending on which domain is used as query; if so, the number presented is the average result.
Mentions: Non-metric multidimensional scaling [34] was used (see Methods) to construct a two-dimensional representation of the similarity data (Figure 3A) in which the domains are positioned so that the distances between them reflects as much as possible the original dissimilarity values. The resulting configuration shows a striking bipartitioning of the domains that recapitulates whether they are first or second domains. Furthermore, the domains nearest the notional "boundary" between the two clusters are EamA-1 (DUF6-1) and EamA-2 (DUF6-2). Our interpretation of this is that it suggests that EamA was the original family from which the other four nucleotide sugar transporter families evolved.

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
Related in: MedlinePlus