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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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Breadth-first clustering of first domain of 19 DMTs using HHsearch HMMs. This figure was prepared using HHsearch all-against-all comparison of first domain of DMTs, to establish closest neighbor of each DMT. The arrows indicate in relation to which family the neighbor is closest, and the HHsearch score is printed in red next to the arrow (giving the uni-directional HHsearch score when the query family is used). Bi-directional arrows indicate cases where there is a reciprocal nearest neighbor relationship; in such cases the HHsearch score represents the average of the two measurements. The gingerbread man icons indicate which families are present in H. sapiens. No arrows are drawn from Cation and Zip, because their nearest neighbors (DUF1632 and DUF486) are very distant: only 3.2 and 5.4% HHsearch probability. Using the Phobius (v1.04) prediction [30], the prevalent membrane orientation is indicated in the figure as the cytosol being in the upper direction of the figure, and the lower direction representing Golgi/endoplasmatic reticuluum/extracellular space. Three clusters are defined: EamA (purple; based on nearest neighbor principle), DUF1632 (green; based on membrane orientation), and metal transporters (turquoise; based on TM and substrate profile). The schematic figure of example structures were drawn using TMRPres2D [36] and InkScape vector graphics editor (v0.47): SLC35B3 (UAA); C1ORF91 (UPF0546); [WormBase:ZC250.3] (NST); SLC35C2 (TPT); SLC35C1 (EamA); SLC35F1 (DUF914); NIPAL1 (DUF803); BOTT52 (DUF486); [UniProt:Q13PK0] (UPF0060); [UniProt:Q7B1Y7] (MDR); [UniProt:Q55C66] (CRT-like); [UniProt:A4A8W4] (FAE 3-kCoA syn1); [UniProt:Q99VZ6] (DUF606); [UniProt:Q9CDF7] (Sugar tranport); [UniProt:Q93P85] (RhaT); TMEM144 (DUF1632); [UniProt:A3IRG4] (CRCB); SLC39A2 (ZIP); SLC30A1 (Cation efflux).
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Figure 5: Breadth-first clustering of first domain of 19 DMTs using HHsearch HMMs. This figure was prepared using HHsearch all-against-all comparison of first domain of DMTs, to establish closest neighbor of each DMT. The arrows indicate in relation to which family the neighbor is closest, and the HHsearch score is printed in red next to the arrow (giving the uni-directional HHsearch score when the query family is used). Bi-directional arrows indicate cases where there is a reciprocal nearest neighbor relationship; in such cases the HHsearch score represents the average of the two measurements. The gingerbread man icons indicate which families are present in H. sapiens. No arrows are drawn from Cation and Zip, because their nearest neighbors (DUF1632 and DUF486) are very distant: only 3.2 and 5.4% HHsearch probability. Using the Phobius (v1.04) prediction [30], the prevalent membrane orientation is indicated in the figure as the cytosol being in the upper direction of the figure, and the lower direction representing Golgi/endoplasmatic reticuluum/extracellular space. Three clusters are defined: EamA (purple; based on nearest neighbor principle), DUF1632 (green; based on membrane orientation), and metal transporters (turquoise; based on TM and substrate profile). The schematic figure of example structures were drawn using TMRPres2D [36] and InkScape vector graphics editor (v0.47): SLC35B3 (UAA); C1ORF91 (UPF0546); [WormBase:ZC250.3] (NST); SLC35C2 (TPT); SLC35C1 (EamA); SLC35F1 (DUF914); NIPAL1 (DUF803); BOTT52 (DUF486); [UniProt:Q13PK0] (UPF0060); [UniProt:Q7B1Y7] (MDR); [UniProt:Q55C66] (CRT-like); [UniProt:A4A8W4] (FAE 3-kCoA syn1); [UniProt:Q99VZ6] (DUF606); [UniProt:Q9CDF7] (Sugar tranport); [UniProt:Q93P85] (RhaT); TMEM144 (DUF1632); [UniProt:A3IRG4] (CRCB); SLC39A2 (ZIP); SLC30A1 (Cation efflux).

Mentions: Three clusters are discovered in a "breadth-first" clustering made using HHsearch probability to closest neighbor for the DMT-1 domain. These clusters are named EamA, DUF1632, and metal transporters [Figure 5], from their human or most notable member family. The clustering principle is to join any nearest neighbor, making the clustering independent of any cutoff.


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)

Breadth-first clustering of first domain of 19 DMTs using HHsearch HMMs. This figure was prepared using HHsearch all-against-all comparison of first domain of DMTs, to establish closest neighbor of each DMT. The arrows indicate in relation to which family the neighbor is closest, and the HHsearch score is printed in red next to the arrow (giving the uni-directional HHsearch score when the query family is used). Bi-directional arrows indicate cases where there is a reciprocal nearest neighbor relationship; in such cases the HHsearch score represents the average of the two measurements. The gingerbread man icons indicate which families are present in H. sapiens. No arrows are drawn from Cation and Zip, because their nearest neighbors (DUF1632 and DUF486) are very distant: only 3.2 and 5.4% HHsearch probability. Using the Phobius (v1.04) prediction [30], the prevalent membrane orientation is indicated in the figure as the cytosol being in the upper direction of the figure, and the lower direction representing Golgi/endoplasmatic reticuluum/extracellular space. Three clusters are defined: EamA (purple; based on nearest neighbor principle), DUF1632 (green; based on membrane orientation), and metal transporters (turquoise; based on TM and substrate profile). The schematic figure of example structures were drawn using TMRPres2D [36] and InkScape vector graphics editor (v0.47): SLC35B3 (UAA); C1ORF91 (UPF0546); [WormBase:ZC250.3] (NST); SLC35C2 (TPT); SLC35C1 (EamA); SLC35F1 (DUF914); NIPAL1 (DUF803); BOTT52 (DUF486); [UniProt:Q13PK0] (UPF0060); [UniProt:Q7B1Y7] (MDR); [UniProt:Q55C66] (CRT-like); [UniProt:A4A8W4] (FAE 3-kCoA syn1); [UniProt:Q99VZ6] (DUF606); [UniProt:Q9CDF7] (Sugar tranport); [UniProt:Q93P85] (RhaT); TMEM144 (DUF1632); [UniProt:A3IRG4] (CRCB); SLC39A2 (ZIP); SLC30A1 (Cation efflux).
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Figure 5: Breadth-first clustering of first domain of 19 DMTs using HHsearch HMMs. This figure was prepared using HHsearch all-against-all comparison of first domain of DMTs, to establish closest neighbor of each DMT. The arrows indicate in relation to which family the neighbor is closest, and the HHsearch score is printed in red next to the arrow (giving the uni-directional HHsearch score when the query family is used). Bi-directional arrows indicate cases where there is a reciprocal nearest neighbor relationship; in such cases the HHsearch score represents the average of the two measurements. The gingerbread man icons indicate which families are present in H. sapiens. No arrows are drawn from Cation and Zip, because their nearest neighbors (DUF1632 and DUF486) are very distant: only 3.2 and 5.4% HHsearch probability. Using the Phobius (v1.04) prediction [30], the prevalent membrane orientation is indicated in the figure as the cytosol being in the upper direction of the figure, and the lower direction representing Golgi/endoplasmatic reticuluum/extracellular space. Three clusters are defined: EamA (purple; based on nearest neighbor principle), DUF1632 (green; based on membrane orientation), and metal transporters (turquoise; based on TM and substrate profile). The schematic figure of example structures were drawn using TMRPres2D [36] and InkScape vector graphics editor (v0.47): SLC35B3 (UAA); C1ORF91 (UPF0546); [WormBase:ZC250.3] (NST); SLC35C2 (TPT); SLC35C1 (EamA); SLC35F1 (DUF914); NIPAL1 (DUF803); BOTT52 (DUF486); [UniProt:Q13PK0] (UPF0060); [UniProt:Q7B1Y7] (MDR); [UniProt:Q55C66] (CRT-like); [UniProt:A4A8W4] (FAE 3-kCoA syn1); [UniProt:Q99VZ6] (DUF606); [UniProt:Q9CDF7] (Sugar tranport); [UniProt:Q93P85] (RhaT); TMEM144 (DUF1632); [UniProt:A3IRG4] (CRCB); SLC39A2 (ZIP); SLC30A1 (Cation efflux).
Mentions: Three clusters are discovered in a "breadth-first" clustering made using HHsearch probability to closest neighbor for the DMT-1 domain. These clusters are named EamA, DUF1632, and metal transporters [Figure 5], from their human or most notable member family. The clustering principle is to join any nearest neighbor, making the clustering independent of any cutoff.

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