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Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health.

Pochini L, Scalise M, Galluccio M, Indiveri C - Front Chem (2014)

Bottom Line: Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature.The last two are associated to the ancillary CD98 protein.Some models of rat and human glutamine transporters highlight very similar structures between the orthologs.

View Article: PubMed Central - PubMed

Affiliation: Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria Arcavacata di Rende, Italy.

ABSTRACT
Glutamine together with glucose is essential for body's homeostasis. It is the most abundant amino acid and is involved in many biosynthetic, regulatory and energy production processes. Several membrane transporters which differ in transport modes, ensure glutamine homeostasis by coordinating its absorption, reabsorption and delivery to tissues. These transporters belong to different protein families, are redundant and ubiquitous. Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature. Function of glutamine transporters is studied in cells over-expressing the transporters or, more recently in proteoliposomes harboring the proteins extracted from animal tissues or over-expressed in microorganisms. The role of the glutamine transporters is linked to their transport modes and coupling with Na(+) and H(+). Most transporters share specificity for other neutral or cationic amino acids. Na(+)-dependent co-transporters efficiently accumulate glutamine while antiporters regulate the pools of glutamine and other amino acids. The most acknowledged glutamine transporters belong to the SLC1, 6, 7, and 38 families. The members involved in the homeostasis are the co-transporters B0AT1 and the SNAT members 1, 2, 3, 5, and 7; the antiporters ASCT2, LAT1 and 2. The last two are associated to the ancillary CD98 protein. Some information on regulation of the glutamine transporters exist, which, however, need to be deepened. No information at all is available on structures, besides some homology models obtained using similar bacterial transporters as templates. Some models of rat and human glutamine transporters highlight very similar structures between the orthologs. Moreover the presence of glycosylation and/or phosphorylation sites located at the extracellular or intracellular faces has been predicted. ASCT2 and LAT1 are over-expressed in several cancers, thus representing potential targets for pharmacological intervention.

No MeSH data available.


Related in: MedlinePlus

Homology models of LAT2 human and rat transporters. The homology structural models of rat (Chaudhry et al.) and human (purple) LAT2 were constructed as described in Figure 4 using as template the structure of the arginine/agmantine antiporter AdiC from E. coli (PDB 3OB6). Superposition of the rat and human structural models was performed by VMD 1.9.1. C154 of the human protein involved in disulfide bridge with 4F2hc is highlighted in yellow; putative PKC and PKA phosphorylation sites are highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
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Figure 6: Homology models of LAT2 human and rat transporters. The homology structural models of rat (Chaudhry et al.) and human (purple) LAT2 were constructed as described in Figure 4 using as template the structure of the arginine/agmantine antiporter AdiC from E. coli (PDB 3OB6). Superposition of the rat and human structural models was performed by VMD 1.9.1. C154 of the human protein involved in disulfide bridge with 4F2hc is highlighted in yellow; putative PKC and PKA phosphorylation sites are highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.

Mentions: Further structural features were already described for LAT1 and LAT2 transporters: potential casein kinase II-dependent phosphorylation site(s), PKC phosphorylation motifs, tyrosine kinase dependent phosphorylation sites (Prasad et al., 1999; Segawa et al., 1999). The alignment of the rat and human LAT2 sequences shows high percentage of identity (92%, not shown). This data has been confirmed by the superimposition of the two structural model (RMSD 0.66) obtained by using the structure of ADiC transporter as template (PDB 3OB6; Figure 6). Differently from the other glutamine transporters, Scan-Prosite analysis predicts lack of glycosylation sites. For these transporters the targeting to the membrane is guaranteed by their binding partner (Costa et al., 2013; Rosell et al., 2014). This interaction is mediated by disulfide bridge involving C154 for the human isoform and C155 for the rat isoform exposed toward the extracellular side of the proteins (Figure 6). Both the isoforms contain 11 Cys residues. No metal binding motif has been found. On the opposite side the human model contains 3 serine residues (S179, S337, S487), putative PKC phosphorylation sites and a threonine residue (T363), putative PKA phosphorylation site. These sites are exposed toward the cytosolic side of the protein. The rat and human proteins show nearly overlapping predicted structures (Figure 6).


Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health.

Pochini L, Scalise M, Galluccio M, Indiveri C - Front Chem (2014)

Homology models of LAT2 human and rat transporters. The homology structural models of rat (Chaudhry et al.) and human (purple) LAT2 were constructed as described in Figure 4 using as template the structure of the arginine/agmantine antiporter AdiC from E. coli (PDB 3OB6). Superposition of the rat and human structural models was performed by VMD 1.9.1. C154 of the human protein involved in disulfide bridge with 4F2hc is highlighted in yellow; putative PKC and PKA phosphorylation sites are highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127817&req=5

Figure 6: Homology models of LAT2 human and rat transporters. The homology structural models of rat (Chaudhry et al.) and human (purple) LAT2 were constructed as described in Figure 4 using as template the structure of the arginine/agmantine antiporter AdiC from E. coli (PDB 3OB6). Superposition of the rat and human structural models was performed by VMD 1.9.1. C154 of the human protein involved in disulfide bridge with 4F2hc is highlighted in yellow; putative PKC and PKA phosphorylation sites are highlighted in green. N- and C- terminals of rat and human proteins are nearly coincident and highlighted by single N and C.
Mentions: Further structural features were already described for LAT1 and LAT2 transporters: potential casein kinase II-dependent phosphorylation site(s), PKC phosphorylation motifs, tyrosine kinase dependent phosphorylation sites (Prasad et al., 1999; Segawa et al., 1999). The alignment of the rat and human LAT2 sequences shows high percentage of identity (92%, not shown). This data has been confirmed by the superimposition of the two structural model (RMSD 0.66) obtained by using the structure of ADiC transporter as template (PDB 3OB6; Figure 6). Differently from the other glutamine transporters, Scan-Prosite analysis predicts lack of glycosylation sites. For these transporters the targeting to the membrane is guaranteed by their binding partner (Costa et al., 2013; Rosell et al., 2014). This interaction is mediated by disulfide bridge involving C154 for the human isoform and C155 for the rat isoform exposed toward the extracellular side of the proteins (Figure 6). Both the isoforms contain 11 Cys residues. No metal binding motif has been found. On the opposite side the human model contains 3 serine residues (S179, S337, S487), putative PKC phosphorylation sites and a threonine residue (T363), putative PKA phosphorylation site. These sites are exposed toward the cytosolic side of the protein. The rat and human proteins show nearly overlapping predicted structures (Figure 6).

Bottom Line: Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature.The last two are associated to the ancillary CD98 protein.Some models of rat and human glutamine transporters highlight very similar structures between the orthologs.

View Article: PubMed Central - PubMed

Affiliation: Department DiBEST (Biologia, Ecologia, Scienze della Terra) Unit of Biochemistry and Molecular Biotechnology, University of Calabria Arcavacata di Rende, Italy.

ABSTRACT
Glutamine together with glucose is essential for body's homeostasis. It is the most abundant amino acid and is involved in many biosynthetic, regulatory and energy production processes. Several membrane transporters which differ in transport modes, ensure glutamine homeostasis by coordinating its absorption, reabsorption and delivery to tissues. These transporters belong to different protein families, are redundant and ubiquitous. Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature. Function of glutamine transporters is studied in cells over-expressing the transporters or, more recently in proteoliposomes harboring the proteins extracted from animal tissues or over-expressed in microorganisms. The role of the glutamine transporters is linked to their transport modes and coupling with Na(+) and H(+). Most transporters share specificity for other neutral or cationic amino acids. Na(+)-dependent co-transporters efficiently accumulate glutamine while antiporters regulate the pools of glutamine and other amino acids. The most acknowledged glutamine transporters belong to the SLC1, 6, 7, and 38 families. The members involved in the homeostasis are the co-transporters B0AT1 and the SNAT members 1, 2, 3, 5, and 7; the antiporters ASCT2, LAT1 and 2. The last two are associated to the ancillary CD98 protein. Some information on regulation of the glutamine transporters exist, which, however, need to be deepened. No information at all is available on structures, besides some homology models obtained using similar bacterial transporters as templates. Some models of rat and human glutamine transporters highlight very similar structures between the orthologs. Moreover the presence of glycosylation and/or phosphorylation sites located at the extracellular or intracellular faces has been predicted. ASCT2 and LAT1 are over-expressed in several cancers, thus representing potential targets for pharmacological intervention.

No MeSH data available.


Related in: MedlinePlus