2.A.53 The Sulfate Permease (SulP) Family

The SulP family is a large and ubiquitous family with members derived from archaea, bacteria, fungi, plants and animals. Many organisms including Bacillus subtilis, Synechocystis sp, Saccharomyces cerevisiae, Arabidopsis thaliana and Caenorhabditis elegans possess multiple SulP family paralogues. Many of these proteins are functionally characterized, and most are inorganic anion uptake transporters or anion:anion exchange transporters. Some transport their substrate(s) with high affinities, while others transport it or them with relatively low affinities. Many function by SO42-:H+ symport, but SO42-:HCO3-, or more generally, anion:anion antiport has been reported for several homologues. For example the mouse homologue, Slc26a6 (TC #2.A.53.2.7), can transport sulfate, formate, oxalate, chloride and bicarbonate, exchanging any one of these anions for another (Jiang et al., 2002). A cyanobacterial homologue can transport nitrate (Maeda et al., 2006). Some members can function as channels (Ohana et al., 2011). 2.A.53.2.3 (SLC26a3) and SLC26a6 (2.A.53.2.7 and 8) can function as carriers or channels, depending on the transported anion (Ohana et al., 2011). In these porters, mutating a glutamate, also involved in transport in the CIC family (2.A.49), (E357A in SLC26a6) created a channel out of the carrier. It also changed the stoichiometry from 2Cl-/HCO3- to 1Cl-/HCO3- (Ohana et al., 2011).

Some paralogs function as anion exchangers, others as anion channels, and one - prestin (SLC26A5) - represents a membrane-bound motor protein in outer hair cells of the inner ear. All SulPs appear to be assembled as dimers composed of two identical subunits (Detro-Dassen et al., 2007). Co-expression of two mutant prestins with distinct voltage-dependent capacitances results in motor proteins with novel electrical properties, indicating that the two subunits do not function independently. An evolutionarily conserved dimeric quaternary structure may represent the native and functional state of SulP transporters (Detro-Dassen et al., 2007). A low resolution structure of a bacterial SulP transporter revealed a dimeric stoichiometry, stabilized via its transmembrane core and mobile intracellular domains. The cytoplasmic STAS domain projects away from the transmembrane domain and is not involved in dimerization. The structure suggests that large movements of the STAS domain underlie the conformational changes that occur during transport.

The bacterial proteins vary in size from 434 residues to 573 residues with only a few exceptions. The eukaryotic proteins vary in size from 611 residues to 893 residues with a few exceptions. Thus, the eukaryotic proteins are usually larger than the prokaryotic homologues. These proteins exhibit 10-13 putative transmembrane α-helical spanners (TMSs) depending on the protein.

One of the distant SulP homologues has been shown to be a bicarbonate:Na+ symporter (TC#2.A.53.5.1) (Price et al., 2004). Bioinformatic work has identified additional homologues with fused domains (Felce and Saier, 2005). Some of these fused proteins have SulP homologues fused to carbonic anhydrase homologues (TC #2.A.53.8.1). These are also presumed to be bicarbonate uptake permeases (Felce and Saier, 2005). Another has SulP fused to Rhodanese, a sulfate:cyanide sulfotransferase (TC #2.A.53.9.1). This SulP homologue is presumably a sulfate transporter.

One member of the SulP family, SLC26a3, has been knocked out in mice (Schweinfest et al., 2006). Apical membrane chloride/base exchange activity was sharply reduced, and luminal content was more acidic in slc26a3-null mouse colon. The epithelial cells in the colon displayed unique adaptive regulation of ion transporters; NHE3 expression was enhanced in the proximal and distal colon, whereas colonic H,K-ATPase and the epithelial sodium channel showed massive up-regulation in the distal colon. Plasma aldosterone was increased in slc26a3-null mice. Thus, slc26a3 is the major apical chloride/base exchanger and is essential for the absorption of chloride in the colon. In addition, slc26a3 regulates colonic crypt proliferation. Deletion of slc26a3 results in chloride-rich diarrhea and is associated with compensatory adaptive up-regulation of ion-absorbing transporters.

MOT1 from Arabidopsis thaliana (TC# 2.A.53.11.1, 456aas; 8-10 TMSs), a distant homologue of the SulP and BenE (2.A.46) families, is expressed in both roots and shoots, and is localized to plasma membranes and intracellular vesicles. MOT1 is required for efficient uptake and translocation of molybdate as well as for normal growth under conditions of limited molybdate supply. Kinetic studies in yeast revealed that the K(m) value of MOT1 for molybdate is approximately 20 nM. Mo uptake by MOT1 in yeast is not affected by the presence of sulfate. MOT1 did not complement a sulfate transporter-deficient yeast mutant strain (Tomatsu et al., 2007). MOT1 is thus specific for molybdate. The high affinity of MOT1 allows plants to obtain scarce Mo from soil when its concentration is about 10nM.

SLC26 proteins function as anion exchangers and Cl- channels. Ousingsawat et al. (2012) examined the functional interaction between CFTR and SLC26A9 in polarized airway epithelial cells and in non-polarized HEK293 cells expressing CFTR and SLC26A9 (2.A.56.2.10). They found that SLC26A9 provides a constitutively active basal Cl- conductance in polarized grown CFTR-expressing CFBE airway epithelial cells, but not in cells expressing F508del-CFTR. In polarized CFTR-expressing cells, SLC26A9 also contributes to both Ca2+ - and CFTR-activated Cl- secretion. In contrast in non-polarized HEK293 cells co-expressing CFTR/SLC26A9, the baseline Cl- conductance provided by SLC26A9 was inhibited during activation of CFTR. Thus, SLC26A9 and CFTR behave differentially in polarized and non-polarized cells, explaining earlier conflicting data.

3-d structural data confirmed primary sequence analyses that came to the conclusion that the SulP family is a member of the APC superfamily (Vastermark et al. 2014), and this conclusion has been further verified (Chang and Geertsma 2017).  N-glycosylation plays three roles in the functional expression of SLC26 proteins: 1) to retain mis-folded proteins in the ER, 2) to stabilize the protein at the cell surface, and 3) to maintain the transport protein in a functional state (Rapp et al. 2018).

The generalized transport reactions catalyzed by SulP family proteins are:

(1) SO42- (out) + nH+ (out) → SO42- (in) + nH+ (in)

(2) SO42- (out) + nHCO3- (in) ⇌ SO42- (in) + nHCO3- (out)

(3) I- and other anions (out) ⇌ I- and other anions (in)

(4) HCO3-(out) + nH+(out) → HCO3- (in) + nH+ (in)



This family belongs to the APC Superfamily.

 

References:

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Examples:

TC#NameOrganismal TypeExample
2.A.53.1.1High-affinity sulfate permease Yeast Sulfate permease of Saccharomyces cerevisiae
 
2.A.53.1.10 solute carrier family 26, member 11AnimalsSLC26A11 of Homo sapiens
 
2.A.53.1.11Putative sulfate transporter YPR003CFungiYPR003C of Saccharomyces cerevisiae
 
2.A.53.1.12

Symbiotic sulfate transporter-1, SST1 of 645 aas.  Expressed only in the symbiosome membrane of rhizobial nodules; transports sulfate from the plant cell cytoplasm to the intracellular rhizobia, where the nutrient is essential for protein and cofactor synthesis, including nitrogenase biosynthesis (Krusell et al. 2005).

Plants

SST1 of Lotus japonicus (Lotus corniculatus var. japonicus)

 
2.A.53.1.13

High affinity sulfate transporter, SUL-2/SUL2/SEL2, of 893 aas and 10 - 12 TMSs. May be a "transceptor", combining transport and receptor functions (Diallinas 2017).

SUL-2 of Saccharomyces cerevisiae

 
2.A.53.1.2Sulfate permease II Fungi Sulfate permease of Neurospora crassa
 
2.A.53.1.3The molybdate (high affinity)/Sulfate (lower affinity) transporter, ShsT1 (Fitzpatrick et al., 2008).Plants ShsT1 of Stylosanthes hamata (P53391)
 
2.A.53.1.4Low-affinity sulfate:H+ symporter, Sut3 Plants Low-affinity sulfate transporter3, Sut3 of Stylosanthes hamata
 
2.A.53.1.5Early Nodulin 70, Nod70 Plants Nod70 of Glycine max
 
2.A.53.1.6

The sulfate transporter, Sultr1.2 with C-terminal STAS domain that is required both for activity and biogenesis/stability (Shibagaki and Grossman, 2006). It physically interacts with 0-acetylserine (thiol)lyase (cysteine synthetase) via its STAS domain. This interaction stimulates the activity of 0-acetylserine (thiol)lyase while inhibiting the SULTR1;2 transport activity. SULTR1.1 (TC# 2.A.53.1.7) interacts with 0-acetylserine (thiol)lyase but this interaction does not stimulate its activity (Shibagaki and Grossman, 2010).

Plants

Sultr1.2 of Arabidopsis thaliana (Q9MAX3)

 
2.A.53.1.7High affinity sulfate transporter, Sultr1.1 regulated differently from Sultr1.2 (2.A.53.1.6) (Rouached et al., 2008)PlantsSultr1.1 of Arabidopsis thaliana (Q9SAY1)
 
2.A.53.1.8

The proton:sulfate symporter, SulP

Algae

SulP of Chlamydomonas reinhardtii (A8J6J0)

 
2.A.53.1.9

Slc26a11 Cl-/oxalate or sulfate (but not bicarbonate) exchanger (Stewart et al., 2011).

Animals

Slc26a11 of Cavia porcellus (G3C7W6)

 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
2.A.53.2.1

Sulfate/anion transporter (diastrophic dysplasia protein) (SLC26A2). It catalyzes electroneutral SO4-, OH- and Cl- exchange regulated by extracellular Cl- (Ohana et al., 2011).

AnimalsSLC26A2 of Homo sapiens
 
2.A.53.2.10

The anion exchanger, channel and Na+-transporter, SLC26a9 (Chang et al. 2009). Differential contributions and interactions of SLC26A9 with CFTR to Cl- conductance in polarized and non-polarized epithelial cells have been demonstrated (Ousingsawat et al., 2012). Slc26a9 (-/-) mice have reduced gastric acid secretion (Chen et al., 2012). Polymorphisms in the human orthologue lead to altered activity and levels (Chen et al., 2012).

Animals

SLC26a9 of Mus musculus (Q8BU91)

 
2.A.53.2.11

Guinea pig Slc26a3 electroneutral Cl-/HCO3- exchanger (does not transport oxalate or sulfate). (Stewart et al., 2011).

Animals

Slc26a3 of Cavia porcellus (G3C7W5)

 
2.A.53.2.12

Slc26a6 Cl-/oxalate, sulfate or bicarbonate exchanger (Stewart et al., 2011).

Animals

Slc26a6 of Cavia porcellus (G3C7W4)

 
2.A.53.2.13 solute carrier family 26, member 10AnimalsSLC26A10 of Homo sapiens
 
2.A.53.2.14 solute carrier family 26, member 8AnimalsSLC26A8 of Homo sapiens
 
2.A.53.2.15

Solute carrier family 26 member 9 (Anion transporter/exchanger protein 9).  May play a role in chronic inflammatory airway diseases (Sala-Rabanal et al. 2015).

Animals

SLC26A9 of Homo sapiens

 
2.A.53.2.16

Sulfate anion transporter 1 (SAT-1 or SAT1) (Solute carrier family 26 member 1); anion exchanger.  Transports chloride, sulfate, bicarbonate and oxalate (Regeer et al. 2003; Lee et al. 2003).  The mouse and rat orthologues have the same specificities and functions. Loss in mice  is associated with hyperoxalurea and calcium oxalate kidney stones, and specific mutations when heterozygous in humans cause urolithiasis (Dawson et al. 2013).  When homozygous, they can cause severe nephrocalcinosis.

Animals

SLC26A1 of Homo sapiens

 
2.A.53.2.17

Pendrin (Sodium-independent chloride/iodide/bicarbonate transporter) (Solute carrier family 26 member 4, Slc26a4).  Involved in ion homeostasis of the endolymph of the inner ear.  Missense mutations cause sensorineuronal hearing loss, but salicylate (aspirin) restored transport function by allowing transport from cytosolic sites to the plasma membrane (Ishihara et al. 2010). May also transport cyanate and thiocyanate (Pedemonte et al. 2007). May play a role in chronic inflammatory airway diseases (Sala-Rabanal et al. 2015). SLC26A4 functional expression may reduce or prevent fluctuation of hearing (Nishio et al. 2016).

Animals

SLC26A4 of Homo sapiens

 
2.A.53.2.18

Chloride anion exchanger (Down-regulated in adenoma) (Protein DRA) (Solute carrier family 26 member 3).  The intracellular pH regulates ion exchange (Hayashi et al. 2009). Reduced functional expression of NHE3, and DRA contribute to Cl- and Na+ stool loss in microvillus inclusion disease (MVID) diarrhea (Kravtsov et al. 2016).

Animals

SLC26A3 of Homo sapiens

 
2.A.53.2.19

Prestin (Solute carrier family 26 member 5).  The motor protein responsible for the somatic electromotility of cochlear outer hair cells; essential for normal hearing sensitivity and frequency selectivity of mammals. Prestin transports a wide variety of monovalent and divalent anions. Many SulP transporters in humans are involved in genetic diseases.They have C-terminal hydrophilic STAS domains that are essential for plasma membrane targeting and protein function. The crystal structure of this STAS domain has been solved at 1.57 A resolution (Pasqualetto et al. 2010).  It senses voltage and binds anions for induction of conformational changes (He et al. 2013).  Prestin's 7+7 inverted repeat architecture suggests a central cavity as the substrate-binding site located midway within the anion permeation pathway. Anion binding to this site controls the electromotile activity of prestin (Gorbunov et al. 2014).

Animals

Prestin (SLC26A5) of Homo sapiens

 
2.A.53.2.2Canicular sulfate:HCO3- antiporter (Slc26a1)

Animals

Sulfate transporter 1 of Rattus norvegicus

 
2.A.53.2.20

Sulfate permease family protein 3, Sulp-3

Worm

Sulp-3 of Caenorhabditis elegans

 
2.A.53.2.3

Intestinal down-regulated in adenoma (DRA) protein; HCO3-/Cl- antiporter, SLC26a3 (responsible for congenital chloride-losing diarrhea in humans) (Schweinfest et al., 2006). DRA has 12 putative TMSs and a C-terminal STAS domain required for function and activation of CFTR by DRA (Dorwart et al., 2008). Catalyzes 2Cl-/1HCO3- antiport, Cl-/OH- exchange and sulfate transport (Shcheynikov et al., 2006; Moseley et al., 1999). Loss in mice impairs mucosal HCO3- secretion (Xiao et al., 2012).

Animals

DRA of Mus musculus

 
2.A.53.2.4

Pendrin (Pendred) syndrome (hereditary deafness) anion transporter (Na+-independent). Anions transported: iodide (thyroid gland; apical membrane of follicular epithelium); bicarbonate (kidney; apical membrane of intercalated cells of the cortical collecting duct), chloride, formate, etc. Pendrin probably catalyzes uniport and anion/anion antiport (SLC26A4). It also regulates Na+ absorption by the epithelial Na+ channel (Wall and Pech, 2008). CFTR controls the rate of liquid secretion while pendrin mediates transcellular HCO3- secretion in airway serous cells (Garnett et al., 2011).   A structural model has been presented (Bassot et al. 2016).

Animals

Pendrin of Mus musculus

 
2.A.53.2.5

Prestin, the outer hair cell voltage-sensitive motor protein (voltage sensitivity depends on intracellular Cl- and HCO3- which may bind to prestin). Prestin transports anions including formate and oxalate; transport and voltage-sensing capabilities are independent functions of the same protein (Bai et al., 2009). Prestin-mediated electromotility is a dual-step process: transport of anions by an alternate access cycle, followed by an anion-dependent transition generating electromotility (Schaechinger et al., 2011; McGuire et al., 2011).  A three-dimensional molecular dynamics model of prestin predicted that it contains eight transmembrane spanning segments and two helical re-entry loops. Tyrosyl residues recognize anions, with residues Y367, Y486, Y501 and Y508 contributing to anion binding through anion-pi interactions. Such interactions, sensitive to voltage and mechanical stimulation, confer a capability to perform electromechanical and mechanoelectric conversions (Lovas et al. 2015).

Animals

Prestin of Mus musculus

 
2.A.53.2.6Basolateral kidney cortical collecting duct and parietal cell chloride/sulfate/oxalate permease or channel, SLC26A7 [substrate preference: NO3- >> Cl- = Br- = I- > SO42- = Glucarate-] (minimal OH- and HCO3- transport; regulated by cytoplasmic pH) (Hwan et al., 2005).  May function as a channel (Ohana et al., 2008).
AnimalsSLC26A7 of Homo sapiens
 
2.A.53.2.7

The human Slc26a6 anion exchanger (transports sulfate, formate, oxalate, chloride and bicarbonate in antiport with any one of these anions) (Jiang et al., 2002). However, Cl- and HSO4- are transported slowly; Cl-/HCO3-, Cl-/OH- and Cl-:oxalate exchange reactions are electroneutral (Chernova et al., 2005). (The oxalate nephrolithiasis gene; Clark et al., 2008). Catalyzes 1Cl-/2HCO3- antiport (Shcheynikov et al., 2006; Walker et al., 2010).

AnimalsSLC26A6 of Homo sapiens
 
2.A.53.2.8

The mouse Slc26a6 anion exchanger (same substrate specificity as its human orthologue (2.A.53.2.7)), but Cl- and HSO4- are transported rapidly. Moreover, although Cl-/HCO3- and Cl-/OH- exchange reactions are electroneutral, Cl-:oxalate exchange is electrogenic (Chernova et al., 2005). Also catalyzes Cl-:formate exchange (Knauf et al., 2001).

Animals

Slc26a6 of Mus musculus (AAH28856)

 
2.A.53.2.9The electrogenic divalent anion: chloride exchanger (1:1 stoichiometry) (transports sulfate, chloride, and oxalate) (Schaechinger and Oliver, 2007)AnimalsPrestin homologue of Gallus gallus (A0FKN5)
 
Examples:

TC#NameOrganismal TypeExample
2.A.53.3.1Sulfate permease Bacteria Sulfate permease of Yersinia enterocolitica
 
2.A.53.3.10Uncharacterized vacuolar membrane protein YGR125WFungiYGR125W of Saccharomyces cerevisiae
 
2.A.53.3.11

Bicarbonate transporter, DauA (YchM). Also transports dicarboxylic acids including fumarate, aspartate and succinate, and is therefore designated the dicarboxylic acid uptake system A (DauA) (Karinou et al. 2013) It is the only succinate uptake porter at acidic pHs. The STAS domain forms a complex with the acyl carrier protein, ACP and malonyl-ACP, and the complex has been determined by x-ray crystallography (PDB# 3NY7).  This complex links bicarbonate and dicarboxylate transport in some way with fatty acid biosynthesis (Moraes and Reithmeier 2012).

Bacteria

DauA or YchM of E. coli

 
2.A.53.3.12

A bicarbonate transporter fused to a carbonic anhydrase, Rv3273 (Moraes and Reithmeier 2012).

Bacteria

Rv3273 of Mycobacterium tuberculosis

 
2.A.53.3.13

Fumarate (Na+-independent anion) transporter, SLC26dg of 499 aas and 14 TMSs.  It has an N-terminal Sulfate-tra-GLY domain with a glycine motif of unknown function and a C-terminal STAS (sulfate transporter and antisigma factor antagonist) domain.  The membrane-inserted domain consists of two intertwined inverted repeats of seven transmembrane segments, each resembling the fold of the (unrelated?) transporter, UraA. The structure shows an inward-facing, ligand-free conformation with a potential substrate-binding site at the interface between two helix termini in the center of the membrane (Geertsma et al. 2015). This structure defines the common framework for the diverse functional behavior of the SLC26 family.

SLC26dg of Deinococcus genothermalis

 
2.A.53.3.2

Bicarbonate:Na+ symporter, BicA (Price et al., 2004).  The protein probably has 14 TMSs in a 7 + 7 arrangement (Price and Howitt 2014).

Bacteria

BicA of Synechococcus WH8102 (Q7U617)

 
2.A.53.3.3

12 TMS Na+:bicarbonate symporter, BicA (Price et al., 2004; Shelden et al., 2010) (low affinity but high efficiency).

Cyanobacteria

BicA of Synechococcus sp. PCC7002 (Q14SY0)

 
2.A.53.3.4

SulP homologue with fused C-terminal STAS/Rhodanese domains [Rhodanese is a sulfate:cyanide sulfotransferase.]

Bacteria

SulP homologue from Chloroflexus auranticus (B9LBX9)

 
2.A.53.3.5

SulP homologue with fused C-terminal STAS/CAP-ED domains (function unknown COG0659) (Felce and Saier, 2005)

Bacteria

SulP homologue of Methyloversatilis universalis (F5R8F2)

 
2.A.53.3.6

Nitrate transporter with fused C-terminal STAS/CAP-ED domain, LtnT (Maeda et al., 2006)

Bacteria

LtnT of Synechococcus elongatus (Q5N2Y3)

 
2.A.53.3.7

SulP homologue with fused C-terminal STAS-CAP-ED domain (function unknown) (Felce and Saier, 2005)

Bacteria

SulP homologue of Schizosaccharomyces pombe (Q09764)

 
2.A.53.3.8

SulP homologue with fused C-terminal carbonic anhydrase domain, probable bicarbonate uptake transporter (Felce and Saier, 2005)

Bacteria

SulP homologue of Leptospira interrogans (Q8F8H7)

 
2.A.53.3.9

SulP homologue. The low resolution structure is available (Compton et al., 2011). 

Bacteria

SulP homologue of Yersinia enterocolitica (A1JRS3)

 
Examples:

TC#NameOrganismal TypeExample
2.A.53.4.1Sulfate transporter Bacteria Sulfate transporter of Synechocystis sp.
 
2.A.53.4.2

Sulfate transporter, Rv1739c (Zolotarev et al. 2008).  Its STAS domain binds guanine nucleotides as shown by x-ray chrystalography (PDB# 2KLN; Sharma et al. 2011; Sharma et al. 2012).  Sulfate uptake by Rv1739c requires CysA and its associated sulfate permease activity, and suggest that Rv1739c may be a CysTWA-dependent sulfate transport protein (Zolotarev et al. 2008).

Bacteria

Rv1739c of Mycobacterium tuberculosis

 
Examples:

TC#NameOrganismal TypeExample
2.A.53.5.1

Molybdenum uptake transporter, Mot1 (Tomatsu et al., 2007)

Plants

Mot1 of Arabidopsis thaliana (Q9SL95)

 
2.A.53.5.2Molybdate transporter 1AlgaeMOT1 of Chlamydomonas reinhardtii
 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample