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).

The molecular principles underlying diverse functions of the SLC26 family of proteins have been reviewed (Takahashi and Homma 2024). (i) The basic residue at the anion binding site is essential for both anion antiport of SLC26A4 and motor functions of SLC26A5, and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9; (ii) the conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions; (iii) the hydrophobic interaction between each protomer's last transmembrane helices, TM14, is not of functional significance in SLC26A9 but crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane (Takahashi and Homma 2024).

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.  A strikingly similar homodimeric molecular architecture for several SLC26 members, implies a shared molecular principle, yet these systems differ in function (Takahashi and Homma 2023).  (i) the basic residue at the anion binding site is essential for both anion antiport of SLC26A4 (TC# 2.A.53.2.17) and motor functions of SLC26A5 (TC# 2.A.53.2.19) and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9 (TC# 2.A.53.2.15; (ii) the conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions; (iii) the hydrophobic interaction between each protomer's last transmembrane helices, TM14, is not of functional significance in SLC26A9 but crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane.

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).  A structural basis for functional interactions in dimers of SLC26 transporters has been reported (Chang et al. 2019).  Takahashi and Homma 2023 characterized common vs. distinct molecular mechanisms among the SLC26 proteins using both naturally occurring and artificial missense changes introduced to SLC26A4, SLC26A5, and SLC26A9. They found: (i) the basic residue at the anion binding site is essential for both anion antiport of SLC26A4 and motor functions of SLC26A5, and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9; (ii) the conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions; (iii) the hydrophobic interaction between each protomer's last TMS,, TMS14, is not of functional significance in SLC26A9 but is crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane (Takahashi and Homma 2023).

Sulfate Transport Anti-Sigma antagonist domains (Pfam01740) are found in all branches of life, from eubacteria to mammals, as a conserved fold encoded by highly divergent amino acid sequences. These domains are present as parts of larger SLC26/SulP anion transporters, where the STAS domain is associated with transmembrane anchoring of the larger multidomain protein. Moy and Seshu 2021 STAS Domain only Proteins (SDoPs) in eubacteria, initially described as part of the Bacillus subtilis Regulation of Sigma B (RSB) regulatory system. SDoPs are involved in the regulation of sigma factors through partner-switching mechanisms in various bacteria such as Mycobacterium tuberculosis, Listeria monocytogenes, Vibrio fischeri and Bordetella bronchiseptica, among others. In addition to playing a canonical role in partner-switching with an anti-sigma factor to affect the availability of a sigma factor, several eubacterial SDoPs show additional regulatory roles compared to the original RSB system of B. subtilis (Moy and Seshu 2021). 

(i) The basic residue at the anion binding site is essential for both anion antiport of SLC26A4 and motor functions of SLC26A5, and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9. (ii) The conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions. (iii) The hydrophobic interaction between each protomer's last transmembrane helices, TM14, is not of functional significance in SLC26A9 but crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane (Takahashi and Homma 2023).

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.



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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

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).


SST1 of Lotus japonicus (Lotus corniculatus var. japonicus)


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


Sulfate transporter 4:1, chloroplastic, SULTR4;1, MSH12.1, of 685 aas and 13 - 15 TMSs. It is a H+/sulfate cotransporter that may play a role in the regulation of sulfate assimilation. The structure of AtSULTR4;1, in complex with SO42- at an overall resolution of 2.8 Å has been determined (Wang et al. 2021). AtSULTR4;1 forms a homodimer and has a structural fold typical of the SLC26 family of anion transporters. The bound SO42- is coordinated by side-chain hydroxyls and backbone amides, and further stabilized electrostatically by the conserved Arg393 and two helix dipoles. Proton and SO42- are co-transported, and a proton gradient significantly enhances SO42- transport. Glu347, which is ~7 Å from the bound SO42-, is required for H+-driven transport. The cytosolic STAS domain interacts with the transmembrane domains, and deletion of the STAS domain, or mutations at the interface, compromise dimer formation and reduces SO42- transport, suggesting a regulatory function of the STAS domain (Wang et al. 2021).


SULTR4;1 of Arabidopsis thaliana (Mouse-ear cress)

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

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).


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)

The proton:sulfate symporter, SulP


SulP of Chlamydomonas reinhardtii (A8J6J0)


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


Slc26a11 of Cavia porcellus (G3C7W6)


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

Sulfate/anion transporter (diastrophic dysplasia protein) (SLC26A2). It catalyzes electroneutral SO4-, OH- and Cl- exchange, regulated by extracellular Cl- (Ohana et al., 2011). Congenital chloride diarrhea and inherited skeletal dysplasias are observed in patients with SLC26A2 mutations (Sun et al. 2021). Biji et al. 2022 have expanded the spectrum of SLC26A2-related lethal chondrodysplasia and reported three novel variants correlating clinical severity and protein phenotype within the lethal spectrum of this rare dysplasia.



SLC26A2 of Homo sapiens


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).


SLC26a9 of Mus musculus (Q8BU91)


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


Slc26a3 of Cavia porcellus (G3C7W5)


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


Slc26a6 of Cavia porcellus (G3C7W4)

2.A.53.2.13 solute carrier family 26, member 10AnimalsSLC26A10 of Homo sapiens

Solute exchange carrier family 26, member 8, SLC26A8 or Testis anion transporter 1 (Tat1), of 970 aas and possibly 17 TMSs in a 4 + 4 + 4 + 2 + 3 TMS arrangement.  It acts as a DIDS-sensitive anion exchanger mediating chloride, sulfate and oxalate transport. May fulfill critical anion exchange functions in male germ line during meiosis and hence may play a role in spermatogenesis. It may be involved in a new regulatory pathway linking sulfate transport to RhoGTPase signaling in male germ cells. It is a critical component of the sperm annulus that is essential for correct sperm tail differentiation and motility and hence male fertility, and it may form a molecular complex involved in the regulation of chloride and bicarbonate ions fluxes during sperm capacitation (Toure et al. 2001). It is is a target for inhibition, for use in male contraception, causing inhibition of sperm motility (Mariani et al. 2023).


SLC26A8 or Tat1 of Homo sapiens


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). The Cl--transporting proteins CFTR (TC# 3.A.1.202.1), SLC26A9, and anoctamin (ANO1; ANO6) (see TC family 1.A.17)  all participate in the pathogenic process and clinical outcomes of airway and renal diseases (Kunzelmann et al. 2023). The molecular principles underlying diverse functions of the SLC26 family of proteins (Takahashi and Homma 2023).  (i) The basic residue at the anion binding site is essential for both anion antiport of SLC26A4 and motor functions of SLC26A5, and its conversion to a nonpolar residue is crucial but not sufficient for the fast uncoupled anion transport in SLC26A9; (ii) the conserved polar residues in the N- and C-terminal cytosolic domains are likely involved in dynamic hydrogen-bonding networks and are essential for anion antiport of SLC26A4 but not for motor (SLC26A5) and uncoupled anion transport (SLC26A9) functions; (iii) the hydrophobic interaction between each protomer's last transmembrane helices, TM14, is not of functional significance in SLC26A9 but crucial for the functions of SLC26A4 and SLC26A5, likely contributing to optimally orient the axis of the relative movements of the core domain with respect to the gate domains within the cell membrane (Takahashi and Homma 2023).


SLC26A9 of Homo sapiens


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. SLC26A1 is a major determinant of sulfate homeostasis in humans (Pfau et al. 2023).


SLC26A1 of Homo sapiens


Pendrin (Sodium-independent chloride/iodide/bicarbonate transporter) (Solute carrier family 26 member 4, Slc26a4; PDS).  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). Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral NIS (TC# 2.A.21.5.1) and the apical anion exchanger pendrin (PDS) (Eleftheriadou et al. 2020). Type II alveolar epithelial cell-specific loss of the small GTPase, RhoA, exacerbates allergic airway inflammation through pendrin (Do et al. 2021). Pendrin maintains ion concentrations in the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Variants in the SLC26A4 gene are responsible for sensorineural hearing loss. Although pendrin localizes to the plasma membrane, 8 missense allele products of SLC26A4 were retained in the intracellular region and lost their anion exchange function (Murakoshi et al. 2022). 10 mM salicylate induced the translocation of 4 out of 8 allele products from the intracellular region to the plasma membrane and restored their anion exchanger activities. 2-hydroxybenzyl alcohol restored the localization of the p.H723R allele products of SLC26A4 from the ER to the plasma membrane at a concentration of 1 mM by 3 h after its administration with less cytotoxicity than 10 mM salicylate (Murakoshi et al. 2022). Mutations of coding regions and splice sites of SLC26A4 cause Pendred syndrome and nonsyndromic recessive hearing loss DFNB4. SLC26A4 is an exchanger of anions and bases. The mutant SLC26A4 phenotype is characterized by inner ear malformations, including an enlarged vestibular aqueduct (EVA), incomplete cochlear partition type II and modiolar hypoplasia, progressive and fluctuating hearing loss, and vestibular dysfunction (Honda and Griffith 2022).  Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO3-) exchange for chloride (Cl-) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I-) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter.  Niflumic acid (NFA) inhibits pendrin by competing with anion binding and impeding the structural changes necessary for anion exchange (Wang et al. 2024).


SLC26A4 of Homo sapiens


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). Mutations cause Congenital Chloride Diarrhea (CCD), an autosomal recessive disease in humans.  Upon infection with Salmonella, DRA levels go down, preventing Cl- absorption giving rise to diarrhea (A. Quach, personal communication). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while the Na+-HCO3--cotransporter (NBC-1; TC# 2.A.31.2.12) and Na+-glucose transporter type-2 (SGLT2 or SGLT-2; TC#2.A.1.7.26) were upregulated after kidney transplantation (Velic et al. 2004).


SLC26A3 of Homo sapiens


Prestin (Solute carrier family 26 member 5).  The motor protein responsible for the somatic electromotility of cochlear outer hair cells (OHC); essential for normal hearing sensitivity and frequency selectivity in mammals. Prestin transports a wide variety of monovalent and divalent anions. Many SulP transporters 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 Å 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).  Zhai et al. 2020 studied the maturation of voltage-induced shifts in the Prestin operating point during trafficking. Calmodulin binds to the STAS domain with a calcium-dependent, one-lobe, binding mode (Costanzi et al. 2021). Prestin is the molecular actuator that drives OHC electromotility (eM). eM is mediated by an area motor mechanism, in which prestin proteins act as elementary actuators by changing their area in the membrane in response to changes in membrane potential. The area changes of a large and densely packed population of prestin molecules add up, resulting in macroscopic cellular movement. At the single protein level, this model implies major voltage-driven conformational rearrangements. SLC26 transporters including prestin generally are dimers. Lenz and Oliver 2021 reviewed the structures and discussed insights into a potential molecular mechanism. Distinct conformations were observed when purifying and imaging prestin bound to either its physiological ligand, chloride, or to competitively inhibitory anions, sulfate or salicylate. These structural snapshots indicate that the conformational landscape of prestin includes rearrangements between the two major domains of prestin's transmembrane region (TMD), core and scaffold ('gate') domains. Distinct conformations differ in the area the TMD occupies in the membrane and in their impact on the immediate lipid environment. Both effects can contribute to the generation of membrane deformation and thus may underly electromotility. Possibly, these or similar structural rearrangements are driven by the membrane potential to mediate piezoelectric activity (Lenz and Oliver 2021). Prestin differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. Butan et al. 2022 used cryo-EM to determine prestin's structure at 3.6 Å resolution. Prestin was captured in an inward-open state which may reflect prestin's contracted state. Two well-separated transmembrane (TM) domains and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains form a swapped dimer. The TM domains consist of 14 TMSs in two 7+7 inverted repeats, an architecture first observed in the bacterial symporter UraA. Mutation of prestin's chloride binding site removes salicylate competition with anions while retaining the prestin characteristic displacement currents (Nonlinear Capacitance), undermining the extrinsic voltage sensor hypothesis for prestin function (Butan et al. 2022). A structure-based mechanism for the membrane motor prestin has been presented (Ge et al. 2021). A novel role of the folding equilibrium of the anion-binding site in defining prestin's unique voltage-sensing mechanism and electromotility has been proposed (Lin et al. 2023).


Prestin (SLC26A5) of Homo sapiens

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


Sulfate transporter 1 of Rattus norvegicus


Sulfate permease family protein 3, Sulp-3


Sulp-3 of Caenorhabditis elegans


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).


DRA of Mus musculus


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).


Pendrin of Mus musculus


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).


Prestin of Mus musculus


Basolateral 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).


SLC26A7 of Homo sapiens


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

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).


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)

TC#NameOrganismal TypeExample
2.A.53.3.1Sulfate permease Bacteria Sulfate permease of Yersinia enterocolitica

Vacuolar membrane protein, YGR125W, basic amino acid (arginine, etc.) transporter of 1036 aas and 10 - 13 TMSs (Kawano-Kawada et al. 2021). The membrane domain is found in the central part of the protein, residues 210 - 630 with large hydrophilic N- and C-terminal domains. The large C-terminal domain may be a PE-PGRS family domain, some of which may be outer membrane porins (see TC# 9.B.96), and there may be an additional TMS at the C-terminus. Vacuolar levels of basic amino acids drastically decrease in Δygr125w cells. An expression plasmid of YGR125w with HA3-tag inserted in its N-terminal hydrophilic region restored the vacuolar levels of basic amino acids. Uptake of arginine into vacuolar membrane vesicles depended on HA3-YGR125w expression. A conserved aspartate residue in the first TMS (D223) was indispensable for the accumulation of basic amino acids. YGR125w is also designated VSB1. Thus, Ygr125w/Vsb1 contributes to (1) the uptake of arginine into vacuoles and (2) vacuolar compartmentalization of basic amino acids (Kawano-Kawada et al. 2021).


YGR125W of Saccharomyces cerevisiae


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).


DauA or YchM of E. coli


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


Rv3273 of Mycobacterium tuberculosis


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


Bicarbonate:Na+ symporter of 564 aas and 11 putative TMSs. Crystal structures of the transmembrane domain (BicA(TM)) and the cytoplasmic STAS domain (BicA(STAS)) of BicA were solved (Wang et al. 2019). BicA(TM) was captured in an inward-facing HCO3--bound conformation with a '7+7' fold monomer. HCO3- bound to a cytoplasm-facing hydrophilic pocket within the membrane. BicA(STAS) is a compact homodimer, required for the dimerization of BicA. The dimeric structure of BicA was further analysed using cryo-electron microscopy and physiological analysis of the full-length BicA, and may represent the physiological unit of SLC26-family transporters. Comparing the BicA(TM) structure with the outward-facing transmembrane domain structures of other bicarbonate transporters suggested an elevator transport mechanism that is applicable to the SLC26/4 family of sodium-dependent bicarbonate transporters (Wang et al. 2019).

BicA of Synechocystis sp. PCC6803


Inorganic anion antiporter, SulP, of 11 or 12 TMSs in a possibly 6 or 7 TMS bundle followed by a 5 or 6 TMS bundle.

SulP of Plasmodium falciparum


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


BicA of Synechococcus WH8102 (Q7U617)


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


BicA of Synechococcus sp. PCC7002 (Q14SY0)


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


SulP homologue from Chloroflexus auranticus (B9LBX9)


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


SulP homologue of Methyloversatilis universalis (F5R8F2)


Nitrate transporter with fused C-terminal STAS/CAP-ED domain, LtnT.  The cNMP-binding domain appears to inhibits transport under normal conditions (Maeda et al., 2006).


LtnT of Synechococcus elongatus (Q5N2Y3)


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


SulP homologue of Schizosaccharomyces pombe (Q09764)


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


SulP homologue of Leptospira interrogans (Q8F8H7)


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


SulP homologue of Yersinia enterocolitica (A1JRS3)


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

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).


Rv1739c of Mycobacterium tuberculosis


TC#NameOrganismal TypeExample

High affity mitochondrial molybdate uptake transporter, Mot1 of 456 aas and 11 TMSs (Baxter et al. 2008; Tomatsu et al., 2007).  The transcript level of nitrate reductase, NR1, was highly induced under Mo deficiency in a mot1-1 mutant (Ide et al. 2011).


Mot1 of Arabidopsis thaliana (Q9SL95)


High affinity (~6 nM Km) molybdate transporter 1, Mot1 of 519 aas and 12 TMSs (Tejada-Jiménez et al. 2007). 


MOT1 of Chlamydomonas reinhardtii


Molybdate transporter 2, MOT2, of 464 aas and 10 TMSs. It is required for vacuolar molybdate export during senescence. An N-terminal di-leucine motif is critical for correct subcellular localisation of MOT2, and its activity is required for accumulation of molybdate in Arabidopsis seeds. It is involved in inter-organ translocation (Gasber et al. 2011). 

MOT2 of Arabidopsis thaliana


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample