Sodium-solute symporter

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Sodium:solute symporter family
PDB 3dh4 EBI.png
Structure of Sodium/Sugar symporter with bound Galactose from vibrio parahaemolyticus. [1]
Identifiers
SymbolSSF
Pfam PF00474
InterPro IPR001734
PROSITE PDOC00429
TCDB 2.A.21
OPM superfamily 64
OPM protein 3dh4
CDD cd10322
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 3dh4

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. [2] 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.

Contents

Function

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, the 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. [3] [4]

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. [5] Mechanistic aspects of Na+ binding sites in LeuT-like fold symporters has been discussed in detail. [6] [7]

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. [8]

Structure

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. [9] Residues important for substrate and Na+ binding in PutP are found in TMSs 2, 7 and 9 as well as in adjacent loops. [10] 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:sodium symporter (SSS) family, the Vibrio parahaemolyticus sodium:galactose symporter, vSGLT ( 2XQ2 ​, 3DH4 ​). 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) (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. [11]

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. [12] 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.

Transport reaction

The generalized transport reaction usually catalyzed by the members of this family is: [7] 

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. [10]

Subfamilies

Proteins belonging to the SSS family can be found in the Transporter Classification Database.

Human proteins containing this domain

AIT; SLC5A1; SLC5A10; SLC5A11; SLC5A12; SLC5A2; SLC5A3; SLC5A4; SLC5A5; SLC5A6; SLC5A7; SLC5A8; SLC5A9

See also

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

<span class="mw-page-title-main">Mediated transport</span> Transportation of substances via membrane

Mediated transport refers to transport mediated by a membrane transport protein. Substances in the human body may be hydrophobic, electrophilic, contain a positively or negatively charge, or have another property. As such there are times when those substances may not be able to pass over the cell membrane using protein-independent movement. The cell membrane is imbedded with many membrane transport proteins that allow such molecules to travel in and out of the cell. There are three types of mediated transporters: uniport, symport, and antiport. Things that can be transported are nutrients, ions, glucose, etc, all depending on the needs of the cell. One example of a uniport mediated transport protein is GLUT1. GLUT1 is a transmembrane protein, which means it spans the entire width of the cell membrane, connecting the extracellular and intracellular region. It is a uniport system because it specifically transports glucose in only one direction, down its concentration gradient across the cell membrane.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

The galactose permease or GalP found in Escherichia coli is an integral membrane protein involved in the transport of monosaccharides, primarily hexoses, for utilization by E. coli in glycolysis and other metabolic and catabolic pathways (3,4). It is a member of the Major Facilitator Super Family (MFS) and is homologue of the human GLUT1 transporter (4). Below you will find descriptions of the structure, specificity, effects on homeostasis, expression, and regulation of GalP along with examples of several of its homologues.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

The sodium/phosphate cotransporter is a member of the phosphate:Na+ symporter (PNaS) family within the TOG Superfamily of transport proteins as specified in the Transporter Classification Database (TCDB).

<span class="mw-page-title-main">Symporter</span>

A symporter is an integral membrane protein that is involved in the transport of two different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the cell membrane at the same time, and is, therefore, a type of cotransporter. The transporter is called a symporter, because the molecules will travel in the same direction in relation to each other. This is in contrast to the antiport transporter. Typically, the ion(s) will move down the electrochemical gradient, allowing the other molecule(s) to move against the concentration gradient. The movement of the ion(s) across the membrane is facilitated diffusion, and is coupled with the active transport of the molecule(s). In symport, two molecule move in a 'similar direction' at the 'same time'. For example, the movement of glucose along with sodium ions.

<span class="mw-page-title-main">Sodium/glucose cotransporter 1</span>

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

Multi-antimicrobial extrusion protein (MATE) also known as multidrug and toxin extrusion or multidrug and toxic compound extrusion is a family of proteins which function as drug/sodium or proton antiporters.

<span class="mw-page-title-main">Lactose permease</span>

Lactose permease is a membrane protein which is a member of the major facilitator superfamily. Lactose permease can be classified as a symporter, which uses the proton gradient towards the cell to transport β-galactosides such as lactose in the same direction into the cell.

<span class="mw-page-title-main">Betaine transporter</span> Family of transport proteins

Proteins of the Betaine/Carnitine/Choline Transporter (BCCT) family are found in Gram-negative and Gram-positive bacteria and archaea. The BCCT family is a member a large group of secondary transporters, the APC superfamily. Their common functional feature is that they all transport molecules with a quaternary ammonium group [R-N (CH3)3]. The BCCT family proteins vary in length between 481 and 706 amino acyl residues and possess 12 putative transmembrane α-helical spanners (TMSs). The x-ray structures reveal two 5 TMS repeats with the total number of TMSs being 10. These porters catalyze bidirectional uniport or are energized by pmf-driven or smf-driven proton or sodium ion symport, respectively, or else by substrate:substrate antiport. Some of these permeases exhibit osmosensory and osmoregulatory properties inherent to their polypeptide chains.

The Nucleobase:Cation Symporter-1 (NCS1) Family (TC# 2.A.39) consists of over 1000 currently sequenced proteins derived from Gram-negative and Gram-positive bacteria, archaea, fungi and plants. These proteins function as transporters for nucleobases including purines and pyrimidines. Members of this family possess twelve transmembrane α-helical spanners (TMSs). At least some of them have been shown to function in uptake by substrate:H+ symport mechanism.

The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number. This superfamily has since been expanded to include eighteen different families.

Members of the Alanine or Glycine:Cation Symporter (AGCS) Family (TC# 2.A.25) transport alanine and/or glycine in symport with Na+ and or H+.

The branched chain amino acid:cation symporter (LIVCS) family (TC# 2.A.26) is a member of the APC superfamily. Characterized members of this family transport all three of the branched chain aliphatic amino acids (leucine (L), isoleucine (I) and valine (V)). These proteins are found in Gram-negative and Gram-positive bacteria and function by a Na+ or H+ symport mechanism. They possess about 440 amino acyl residues and display 12 putative transmembrane helical spanners. As of early 2016, no crystal structures for members of the LIVCS family are available on RCSB.

The cation-chloride cotransporter (CCC) family is part of the APC superfamily of secondary carriers. Members of the CCC family are found in animals, plants, fungi and bacteria. Most characterized CCC family proteins are from higher eukaryotes, but one has been partially characterized from Nicotiana tabacum, and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp.. The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family. CCC family proteins are usually large, and possess 12 putative transmembrane spanners (TMSs) flanked by large N-terminal and C-terminal hydrophilic domains.

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

Divalent anion:Na+ symporters were found in bacteria, archaea, plant chloroplasts and animals.

References

  1. ↑ 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. Bibcode:2008Sci...321..810F. doi:10.1126/science.1160406. PMC   3654663 . PMID   18599740.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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   3190740 . PMID   21705334.
  6. ↑ Perez, C; Ziegler, C (May 2013). "Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters" (PDF). Biological Chemistry. 394 (5): 641–8. doi:10.1515/hsz-2012-0336. PMID   23362203. S2CID   207453523.
  7. 1 2 Saier, MH Jr. "2.A.21 The Solute:Sodium Symporter (SSS) Family". Transporter Classification Database. Saier Lab Bioinformatics Group and SDSC.
  8. ↑ Quick M, Loo DD, Wright EM (January 2001). "Neutralization of a conserved amino acid residue in the human Na+/glucose transporter (hSGLT1) generates a glucose-gated H+ channel". The Journal of Biological Chemistry. 276 (3): 1728–34. doi: 10.1074/jbc.M005521200 . PMID   11024018.
  9. ↑ 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.
  10. 1 2 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. S2CID   29235609.
  11. ↑ 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. Bibcode:2008Sci...321..810F. doi:10.1126/science.1160406. PMC   3654663 . PMID   18599740.
  12. ↑ 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. Bibcode:1995JMolE..40..136P. doi:10.1007/bf00167109. PMID   7699720. S2CID   8349319.
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