Summary: Sodium:solute symporter family
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Sodium-solute symporter Edit Wikipedia article
|Sodium:solute symporter family|
Structure of Sodium/Sugar symporter with bound Galactose from vibrio parahaemolyticus.
Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na+ symport.
Sodium/substrate symport (or co-transport) is a widespread mechanism of solute transport across cytoplasmic membranes of pro- and eukaryotic cells. The energy stored in an inwardly directed electrochemical sodium gradient (sodium motive force, SMF) which is used to drive solute accumulation against a concentration gradient. The SMF is generated by primary sodium pumps (e.g. sodium/potassium ATPases, sodium translocating respiratory chain complexes) or via the action of sodium/proton antiporters. Sodium/substrate transporters are grouped in different families based on sequence similarities.
The human placental multivitamin symporter co-transports an anionic vitamin with two Na+. In the rabbit Na+:D-glucose co-transporter, SGLT1, the glucose translocation pathway probably involves TMSs 10-13, and the binding site for the inhibitor, phlorizin, involves loop 13 (residues 604-610). Cation binding in the N-terminal domain may induce transport-related conformational changes. A conserved tyrosine in the first transmembrane segment of solute:sodium symporters is involved in Na+-coupled substrate co-transport. Mechanistic aspects of Na+ binding sites in LeuT-like fold symporters has been discussed in detail.
Substrate Affinity in Humans
In the human homologue (hSGLT1), H+ can replace Na+, but the apparent affinity for glucose reduces 20x from 0.3 mM to 6 mM. The apparent affinity for H+ is 6 μM, 1000x higher than for Na+ (6 mM). The transport stoichiometry is 1 glucose to 2 Na+ or H+. If Asp204 is replaced by glutamate (D204E), the apparent affinity for H+ increases >20x with no change in apparent Na+ affinity. The D204N or D204C mutation promotes phlorizin-sensitive H+ currents that are 10x greater than Na+ currents, and the glucose:H+ stoichiometry is then as great as 1:145. The mutant system thus behaves as a glucose-gated H+ channel.
Proteins of the SSS vary in size from about 400 residues to about 700 residues and probably possess thirteen to fifteen putative transmembrane helical spanners (TMSs). They generally share a core of 13 TMSs, but different members of the family have different numbers of TMSs. A 13 TMS topology with a periplasmic N-terminus and a cytoplasmic C-terminus has been experimentally determined for the proline:Na+ symporter, PutP, of E. coli. Residues important for substrate and Na+ binding in PutP are found in TMSs 2, 7 and 9 as well as in adjacent loops. A 14 TMS topology with periplasmic N- and C-termini has been established for the Vibrio parahaemolyticus SglT carrier. SglT transports sugar:Na with a 1:1 stoichiometry. However, MctP of Rhizobium leguminosarum may take up monocarboxylates via an H+ symport mechanism as a dependency on Na+ could not be demonstrated and uptake was strongly inhibited by 10 μM CCP.
Faham et al., (2008) reported the crystal structure of a member of the solute:soduium symporter (SSS) family, the Vibrio parahaemolyticus sodium:galactose symporter, vSGLT (TC# 2.A.22.4.2) from the NSS family. Modeling the outward-facing conformation based on the LeuT structure, in conjunction with biophysical data, provided insight into structural rearrangements for active transport., ). The approximately 3.0 angstrom structure contains 14 transmembrane α-helices in an inward-facing conformation with a core structure of inverted repeats of 5 TM helices (TM2 to TM6 and TM7 to TM11). Galactose is bound in the center of the core, occluded from the outside solutions by hydrophobic residues. The architecture of the core is similar to that of the leucine transporter (LeuT) (
Some bacterial sensor kinases (e.g., 2.A.21.9.1) have N-terminal, 12 TMS, sensor domains that regulate the C-terminal kinase domains. The latter are homologous to the kinase domain of NtrB and other sensor kinases. The N-terminal sensor domains are homologous, but distantly related to members of the SSS. The closest homologues are PutP of E. coli (2.A.21.2.1) and PanF of E. coli (2.A.21.1.1). Homologous regulatory domains are found in Agrobacterium, Mesorhizobium, Sinorhizobium, Vibrio cholerae and Bacillus species. While it is clear that these domains function as sensors, it is not known if they also transport the small molecules they sense.
The generalized transport reaction usually catalyzed by the members of this family is:
solute (out) + nNa+ (out) → solute (in) + nNa+ (in).
An ordered binding model of sodium/substrate transport suggests that sodium binds to the empty transporter first, thereby inducing a conformational alteration which increases the affinity of the transporter for the solute. The formation of the ternary complex induces another structural change that exposes sodium and substrate to the other site of the membrane. Substrate and sodium are released, and the empty transporter re-orientates in the membrane, allowing the cycle to start again.
Proteins belonging to the SSS family can be found in the Transporter Classification Database.
- Sodium/pantothenate symporter InterPro: IPR011849
- Sodium/proline symporter InterPro: IPR011851
- Cation/acetate symporter ActP InterPro: IPR014083
Human proteins containing this domain
- APC Superfamily
- Transporter Classification Database
- Crystal structures:
- Structure of the K294A mutant of vSGLT (2010):
- Crystal Structure of Sodium/Sugar symporter with bound Galactose from vibrio parahaemolyticus (2008):
- Faham S, Watanabe A, Besserer GM, et al. (August 2008). "The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport". Science. 321 (5890): 810–4. doi:10.1126/science.1160406. PMID 18599740.
- Wong, Foon H.; Chen, Jonathan S.; Reddy, Vamsee; Day, Jonathan L.; Shlykov, Maksim A.; Wakabayashi, Steven T.; Saier, Milton H. (2012-01-01). "The amino acid-polyamine-organocation superfamily". Journal of Molecular Microbiology and Biotechnology. 22 (2): 105–113. doi:10.1159/000338542. ISSN 1660-2412. PMID 22627175.
- Reizer J, Reizer A, Saier Jr MH (1990). "The Na+/pantothenate symporter (PanF) of Escherichia coli is homologous to the Na+/proline symporter (PutP) of E. coli and the Na+/glucose symporters of mammals". Res. Microbiol. 141 (9): 1069–1072. doi:10.1016/0923-2508(90)90080-A. PMID 1965458.
- Reizer J, Reizer A, Saier Jr MH (1994). "A functional superfamily of sodium/solute symporters". Biochim. Biophys. Acta. 1197 (2): 133–136. doi:10.1016/0304-4157(94)90003-5. PMID 8031825.
- Mazier, S; Quick, M; Shi, L (August 19, 2011). "Conserved tyrosine in the first transmembrane segment of solute:sodium symporters is involved in Na+-coupled substrate co-transport.". Journal of Biological Chemistry. 286 (33): 29347–55. doi:10.1074/jbc.M111.263327. PMC . PMID 21705334.
- Perez, C; Ziegler, C (May 2013). "Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters.". Biological Chemistry. 394 (5): 641–8. doi:10.1515/hsz-2012-0336. PMID 23362203.
- Saier, MH Jr. "2.A.21 The Solute:Sodium Symporter (SSS) Family". Transporter Classification Database. Saier Lab Bioinformatics Group and SDSC.
- Quick M1, Loo DD, Wright EM., M; Loo, DD; Wright, EM (January 19, 2001). "Neutralization of a conserved amino acid residue in the human Na+/glucose transporter (hSGLT1) generates a glucose-gated H+ channel.". Journal of Biological Chemistry. 276 (3): 1728–34. doi:10.1074/jbc.m005521200. PMID 11024018.
- Jung, H; Hilger, D; Raba, M (January 1, 2012). "The Na+/L-proline transporter PutP.". Frontiers in Bioscience. 17: 745–59. doi:10.2741/3955. PMID 22201772.
- Jung, H (October 2, 2002). "The sodium/substrate symporter family: structural and functional features.". FEBS. 529 (1): 73–7. doi:10.1016/s0014-5793(02)03184-8. PMID 12354616.
- Faham, S; Watanabe, A; Besserer, GM; Cascio, D; Specht, A; Hirayama, BA; Wright, EM; Abramson, J (August 8, 2008). "The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport.". Science. 321 (5890): 810–4. doi:10.1126/science.1160406. PMID 18599740.
- Pao, GM; Saier, MH Jr. (February 1995). "Response regulators of bacterial signal transduction systems: selective domain shuffling during evolution.". Journal of Molecular Evolution. 40 (2): 136–54. doi:10.1007/bf00167109. PMID 7699720.
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This family includes P33413 which is not in the Prosite entry. Membership of this family is supported by a significant blast score.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR001734
Sodium/substrate symport (or co-transport) is a widespread mechanism of solute transport across cytoplasmic membranes of pro- and eukaryotic cells. Thereby the energy stored in an inwardly directed electrochemical sodium gradient (sodium motive force, SMF) is used to drive solute accumulation against a concentration gradient. The SMF is generated by primary sodium pumps (e.g. sodium/potassium ATPases, sodium translocating respiratory chain complexes) or via the action of sodium/proton antiporters. Sodium/substrate transporters are grouped in different families based on sequence similarities [PUBMED:1965458, PUBMED:8031825].
One of these families, known as the sodium:solute symporter family (SSSF), contains over a hundred members of pro- and eukaryotic origin [PUBMED:12354616]. The average hydropathy plot for SSSF proteins predicts 11 to 15 putative transmembrane domains (TMs) in alpha-helical conformation. A secondary structure model of PutP from Escherichia coli suggests the protein contains 13 TMs with the N terminus located on the periplasmic side of the membrane and the C terminus facing the cytoplasm. The results support the idea of a common topological motif for members of the SSSF. Transporters with a C-terminal extension are proposed to have an additional 14th TM.
An ordered binding model of sodium/substrate transport suggests that sodium binds to the empty transporter first, thereby inducing a conformational alteration which increases the affinity of the transporter for the solute. The formation of the ternary complex induces another structural change that exposes sodium and substrate to the other site of the membrane. Substrate and sodium are released and the empty transporter re-orientates in the membrane allowing the cycle to start again.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Molecular function||transporter activity (GO:0005215)|
|Biological process||transport (GO:0006810)|
|transmembrane transport (GO:0055085)|
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This large superfamily contains a variety of transporters including amino acid permeases that according to TCDB belong to the APC (Amino acid-Polyamine-organoCation) superfamily.
The clan contains the following 20 members:AA_permease AA_permease_2 AA_permease_C Aa_trans BCCT BenE Branch_AA_trans CstA HCO3_cotransp K_trans MFS_MOT1 Na_Ala_symp Nramp SNF Spore_permease SSF Sulfate_transp Transp_cyt_pur Trp_Tyr_perm Xan_ur_permease
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Number in seed:||10|
|Number in full:||14837|
|Average length of the domain:||348.50 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||71.62 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||16|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the SSF domain has been found. There are 6 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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