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24  structures 1350  species 0  interactions 17169  sequences 131  architectures

Family: HCO3_cotransp (PF00955)

Summary: HCO3- transporter family

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Anion exchanger family". More...

Anion exchanger family Edit Wikipedia article

Characterized protein members of the Anion Exchanger (AE) Family (TC# 2.A.31) are found in plants, animals and yeast.

Uncharacterized AE homologues are present in bacteria (e.g., in Enterococcus faecium, 372 aas; gi 22992757; 29% identity in 90 residues). The 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.

Anion Exchangers in Humans

In humans, the AE family is composed of 10 paralogous members, among which are the proteins that perform Na+-independent Cl-HCO3- exchange (e.g., AEs 1-3), Na+-coupled anion exchange (e.g., NDCBE), and electroneutral (e.g., NBCn1) and electrogenic (e.g., NBCe1 and NBCe2) Na/HCO3 cotransport (Piermarini et al., 2007). These proteins are important for the regulation of intracellular pH (pHi and play crucial roles in the epithelial absorption of HCO3-(e.g., in the renal proximal tubule) and secretion of HCO3- (e.g., in the pancreatic duct). All AE proteins are hypothesized to share a similar topology in the cell membrane. They have relatively long cytoplasmic N-terminal domains composed of a few hundred to several hundred residues, followed by 10-14 transmembrane (TM) domains, and end with relatively short cytoplasmic C-terminal domains composed of ~30 to ~90 residues. Although the C-terminal domain comprises a small percentage of the size of the protein, this domain in some cases (i) has PSD-95/Discs Large/ZO-1-binding motifs that may be important for protein-protein interactions (e.g., AE1, AE2, and NBCn1), (ii) is important for trafficking to the cell membrane (e.g., AE1 and NBCe1), and (iii) may provide sites for regulation of transporter function via protein kinase A phosphorylation (e.g., NBCe1).

Anion Exchanger 1

The human AE1 binds carbonic anhydrase II (CAII) forming a 'transport metabolon' as CAII binding activates AE1 transport activity about 10 fold (Sterling et al., 2001). AE1 is also activated by interaction with glycophorin, which also functions to target it to the plasma membrane (Young and Tanner, 2003). The membrane-embedded C-terminal domains may each span the membrane 13-16 times. According to the model of Zhu et al. (2003), it spans the membrane 16 times, 13 times as α-helix, and three times (TMSs 10, 11 and 14) possibly as β-strands. They preferentially catalyze anion exchange (antiport) reactions. Specific point mutations in human anion exchanger 1 (AE1) convert this electroneutral anion exchanger into a monovalent cation conductance. The same transport site within the AE1 spanning domain is involved in both anion exchange and cation transport (Barneaud-Rocca et al., 2011).

AE1 in human red blood cells has been shown to transport a variety of inorganic and organic anions. Divalent anions may be symported with H+. Additionally, it catalyzes flipping of several anionic amphipathic molecules such as sodium dodecyl sulfate (SDS) and phosphatidic acid from one monolayer of the phospholipid bilayer to the other monolayer. The rate of flipping is sufficiently rapid to suggest that this AE1-catalyzed process is physiologically important in red blood cells and possibly in other animal tissues as well. Anionic phospholipids and fatty acids are likely to be natural substrates. However, it should be noted that the mere presence of TMSs enhances the rates of lipid flip-flop (Kol et al., 2001; Sapay et al., 2010).


Other Members of the AE Family

Renal Na+:HCO3- cotransporters have been found to be members of the AE family. They catalyze the reabsorption of HCO3- in the renal proximal tubule in an electrogenic process that is inhibited by typical stilbene inhibitors of AE such as DIDS and SITS. They are also found in many other body tissues. At least two genes encode these symporters in any one mammal. A 10 TMS model has been presented (Romero and Boron, 1999), but this model conflicts with the 14 TMS model proposed for AE1. The transmembrane topology of the human pancreatic electrogenic Na+:HO3- transporter, NBC1, has been studied (Tatishchev et al., 2003). A TMS topology with N- and C-termini in the cytoplasm has been suggested. An extracellular loop determines the stoichiometry of Na+-HCO3- cotransporters (Chen et al., 2011).

In addition to the Na+-independent anion exchangers (AE1-3) and the Na+:HCO3- cotransporters (NBCs) (which may be either electroneutral or electrogenic), a Na+-driven HCO3-/Cl- exchanger (NCBE) has been sequenced and characterized (Wang et al., 2000). It transports Na+ + HCO3- preferentially in the inward direction and H+ + Cl- in the outward direction. This NCBE is widespread in mammalian tissues where it plays an important role in cytoplasmic alkalinization. For example, in pancreatic β-cells, it mediates a glucose-dependent rise in pH related to insulin secretion.

Animal cells in tissue culture expressing the gene-encoding the ABC-type chloride channel protein CFTR (TC #3.A.1.202.1) in the plasma membrane have been reported to exhibit cyclic AMP-dependent stimulation of AE activity. Regulation was independent of the Cl- conductance function of CFTR, and mutations in the nucleotide-binding domain #2 of CFTR altered regulation independently of their effects on chloride channel activity. These observations may explain impaired HCO3- secretion in cystic fibrosis patients.

AE Proteins in Plants and Fungi

Plants and yeast have anion transporters that in both the pericycle cells of plants and the plasma membrane of yeast cells export borate or boric acid (pKa = 9.2) (referred to below as 'boron') (Takano et al., 2002). In A. thaliana, boron is exported from pericycle cells into the root stellar apoplasm against a concentration gradient for uptake into the shoots. In S. cerevisiae, export is also against a concentration gradient. The yeast transporter recognizes HCO3-, I-, Br-, NO3- and Cl-which may be substrates. Tolerance to boron toxicity in cereals is known to be associated with reduced tissue accumulation of boron. Expression of genes from roots of boron-tolerant wheat and barley with high similarity to efflux transporters from Arabidopsis and rice lowered boron concentrations due to an efflux mechanism (Reid, 2007). The mechanism of energy coupling is not known, nor is it known if borate or boric acid is the substrate. Several possibilities (uniport, anion:anion exchange and anion:cation exchange) can account for the data (Takano et al., 2002).

SLC4

The SLC4 family consists of 10 genes (SLC4A1-5; SLC4A7-11). All have similar hydropathy plots-consistent with 10-14 transmembrane segments. Nine encode proteins that transport HCO3-. Functionally, eight of these proteins fall into two major groups: three Cl-HCO3- exchangers (AE1-3) and five Na+-coupled HCO3- transporters (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE). Two of the Na+-coupled transporters (NBCe1, NBCe2) are electrogenic; the other three Na+-coupled HCO3- transporters and all three AEs are electroneutral (Romero et al. 2013). Two others (AE4, SLC4A9 and BTR1, SLC4A11) are not characterized. Most, though not all, are inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS). SLC4 proteins play roles in acid-base homeostasis, transport of H+ or HCO3- by epithelia, as well as the regulation of cell volume and intracellular pH (Romero et al. 2013).

Structure

All AE proteins are hypothesized to share a similar topology in the cell membrane. They have relatively long cytoplasmic N-terminal domains composed of a few hundred to several hundred residues, followed by 10-14 transmembrane (TM) domains, and end with relatively short cytoplasmic C-terminal domains composed of ~30 to ~90 residues. Although the Ct domain comprises a small percentage of the size of the protein, this domain in some cases (i) has PSD-95/Discs Large/ZO-1-binding motifs that may be important for protein-protein interactions (e.g., AE1, AE2, and NBCn1), (ii) is important for trafficking to the cell membrane (e.g., AE1 and NBCe1), and (iii) may provide sites for regulation of transporter function via protein kinase A phosphorylation (e.g., NBCe1).

The crystal structure of AE1 (CTD) at 3.5 angstroms has been determined (Arakawa et al. 2015). The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed identification of the likely anion-binding position in the AE1 (CTD), and to propose a possible transport mechanism that could explain why selected mutations lead to disease. The 3-d structure confirmed that the AE family is a member of the APC superfamily (Vastermark et al. 2014).


Transport Reactions

The physiologically relevant transport reaction catalyzed by anion exchangers of the AE family is:

Cl- (in) + HCO3- (out) ⇌ Cl- (out) + HCO3- (in).

That for the Na+:HCO3- cotransporters is:

Na+ (out) + nHCO3- (out) → Na+ (in) + nHCO3- (in).

That for the Na+/HCO3-:H+/Cl- exchanger is:

Na+ (out) + HCO3- (out) + H+ (in) + Cl- (in) ⇌ Na+ (in) + HCO3- (in) + H+ (out) + Cl- (out).

That for the boron efflux protein of plants and yeast is:

Boron (in) → boron (out)


References

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Bicarbonate transporter proteins". More...

Bicarbonate transporter proteins Edit Wikipedia article

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

HCO3- transporter family Provide feedback

This family contains Band 3 anion exchange proteins that exchange CL-/HCO3- such as P48751. This family also includes cotransporters of Na+/HCO3- such as O15153.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR011531

Bicarbonate (HCO 3 - ) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO 3 - transport modes. Anion exchanger proteins exchange HCO 3 - for Cl - in a reversible, electroneutral manner [ PUBMED:2289848 ]. Na + /HCO 3 - co-transport proteins mediate the coupled movement of Na + and HCO 3 - across plasma membranes, often in an electrogenic manner [ PUBMED:9261985 ]. Na - driven Cl - /HCO 3 - exchange and K + /HCO 3 - exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO 3 - transporters that have been cloned to date (the anion exchangers and Na + /HCO 3 - co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO 3 - and are inhibited by a class of pharmacological agents called disulphonic stilbenes [ PUBMED:9235899 ]. They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

This domain is found at the C terminus of many bicarbonate transport proteins. It is also found in some plant proteins responsible for boron transport [ PUBMED:12447444 ]. In these proteins it covers almost the entire length of the sequence.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan APC (CL0062), which has the following description:

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 21 members:

AA_permease AA_permease_2 AA_permease_C Aa_trans BCCT BenE Branch_AA_trans CstA DUF3360 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

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(66)
Full
(17169)
Representative proteomes UniProt
(26886)
RP15
(2091)
RP35
(5930)
RP55
(12937)
RP75
(17756)
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  Seed
(66)
Full
(17169)
Representative proteomes UniProt
(26886)
RP15
(2091)
RP35
(5930)
RP55
(12937)
RP75
(17756)
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  Seed
(66)
Full
(17169)
Representative proteomes UniProt
(26886)
RP15
(2091)
RP35
(5930)
RP55
(12937)
RP75
(17756)
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Gzipped Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

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.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_1004 (release 3.0)
Previous IDs: Anion_Exchanger;
Type: Family
Sequence Ontology: SO:0100021
Author: Croning MDR, Finn RD , Bateman A
Number in seed: 66
Number in full: 17169
Average length of the domain: 315 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 50.36 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.1 27.0
Noise cut-off 26.9 26.9
Model length: 498
Family (HMM) version: 24
Download: download the raw HMM for this family

Species distribution

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Structures

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 HCO3_cotransp domain has been found. There are 24 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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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A044QXL5 View 3D Structure Click here
A0A044TSW1 View 3D Structure Click here
A0A044VJI2 View 3D Structure Click here
A0A077YZE6 View 3D Structure Click here
A0A077Z004 View 3D Structure Click here
A0A077Z1R0 View 3D Structure Click here
A0A077Z805 View 3D Structure Click here
A0A077ZEC9 View 3D Structure Click here
A0A077ZFU0 View 3D Structure Click here
A0A077ZH71 View 3D Structure Click here
A0A077ZJD9 View 3D Structure Click here
A0A0D2GWD3 View 3D Structure Click here
A0A0G2KM71 View 3D Structure Click here
A0A0I9N7P2 View 3D Structure Click here
A0A0K0E642 View 3D Structure Click here
A0A0K0ED92 View 3D Structure Click here
A0A0K0EDV5 View 3D Structure Click here
A0A0K0EGH8 View 3D Structure Click here
A0A0K0EQH1 View 3D Structure Click here
A0A0N4UCY7 View 3D Structure Click here
A0A0N4UGU2 View 3D Structure Click here
A0A0R0G158 View 3D Structure Click here
A0A0R0GYS7 View 3D Structure Click here
A0A0R4IUL4 View 3D Structure Click here
A0A158Q691 View 3D Structure Click here
A0A175WE11 View 3D Structure Click here
A0A175WEM5 View 3D Structure Click here
A0A1C1CIS4 View 3D Structure Click here
A0A1D6EHS7 View 3D Structure Click here
A0A1D6FF25 View 3D Structure Click here
A0A1D6FM15 View 3D Structure Click here
A0A1D6FQE1 View 3D Structure Click here
A0A1D6KBT2 View 3D Structure Click here
A0A1D6MJY4 View 3D Structure Click here
A0A1D6N7V7 View 3D Structure Click here
A0A1D6PKM6 View 3D Structure Click here
A0A286YA89 View 3D Structure Click here
A0A2K6VW50 View 3D Structure Click here
A0A2R8PYB9 View 3D Structure Click here
A0A2R8Q9J0 View 3D Structure Click here