The anion exchanger family
TC# 2.A.31 also named bicarbonate transporter 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
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochem ...
. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria (e.g., in ''
Enterococcus faecium
''Enterococcus faecium'' is a Gram-positive, gamma-hemolytic or non- hemolytic bacterium in the genus ''Enterococcus''. It can be commensal (innocuous, coexisting organism) in the gastrointestinal tract of humans and animals, but it may also be ...
'', 372 aas; gi 22992757; 29% identity in 90 residues). 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 th
Transporter Classification Database.
Family overview
Bicarbonate (HCO
3 −)
transport
Transport (in British English), or transportation (in American English), is the intentional movement of humans, animals, and goods from one location to another. Modes of transport include air, land ( rail and road), water, cable, pipelin ...
mechanisms are the principal regulators of pH in
animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. Functional studies have suggested different HCO
3 − transport modes.
*
Anion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
exchanger
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s exchange HCO
3 − for
Cl− in a reversible, electroneutral manner.
* Na
+/HCO
3 − co-transport
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 cellul ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s mediate the coupled movement of
Na+ and HCO
3 − across
plasma membranes, often in an electrogenic manner.
Sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
analysis of the two families of HCO
3 − transporters that have been
cloned
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, ...
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.
They share around ~25-30%
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
identity, which is distributed along their entire sequence length, and have similar predicted
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
topologies, suggesting they have ~10
transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
(TM)
domains.
A conserved domain is found at the C terminus of many bicarbonate transport proteins. It is also found in some
plant
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclu ...
proteins responsible for
boron transport.
In these proteins it covers almost the entire length of the
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
.
The
Band 3
Band 3 anion transport protein, also known as anion exchanger 1 (AE1) or band 3 or solute carrier family 4 member 1 (SLC4A1), is a protein that is encoded by the gene in humans.
Band 3 anion transport protein is a phylogenetically-preserved ...
anion exchange proteins that exchange bicarbonate are the most abundant polypeptide in the
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
membrane, comprising 25% of the total membrane protein. The cytoplasmic domain of band 3 functions primarily as an anchoring site for other membrane-associated proteins. Included among the protein ligands of this domain are
ankyrin
Ankyrins are a family of proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral mem ...
, protein 4.2, protein 4.1,
glyceraldehyde-3-phosphate dehydrogenase
Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establish ...
(GAPDH),
phosphofructokinase
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. ...
,
aldolase
Fructose-bisphosphate aldolase (), often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phospha ...
,
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...
, hemichromes, and the
protein tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
(p72syk).
Anion exchangers in humans
In humans, anion exchangers fall under the solute carrier family 4 (SLC4) family, which is composed of 10 paralogous members (SLC4A1-5; SLC4A7-11). Nine encode proteins that transport HCO. Functionally, eight of these proteins fall into two major groups: three Cl-HCO exchangers (AE1-3) and five Na
+-coupled HCO transporters (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE). Two of the Na
+-coupled transporters (NBCe1, NBCe2) are electrogenic; the other three Na
+-coupled HCO transporters and all three AEs are electroneutral.
Two others (AE4, SLC4A9 and BTR1,
SLC4A11
Sodium bicarbonate transporter-like protein 11 is a protein that in humans is encoded by the ''SLC4A11'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...
) 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 HCO by epithelia (e.g. absorption of HCO in the renal proximal tubule, secretion of
HCO in the pancreatic duct), as well as the regulation of cell volume and intracellular pH.
Based on their hydropathy plots all SLC4 proteins are hypothesized to share a similar
topology
In mathematics, topology (from the Greek words , and ) is concerned with the properties of a geometric object that are preserved under continuous deformations, such as stretching, twisting, crumpling, and bending; that is, without closing ...
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
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
domain comprises a small percentage of the size of the protein, this domain in some cases, has (i) 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
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
phosphorylation (e.g., NBCe1).
The SLC4 family comprises the following proteins.
*
SLC4A1
*
SLC4A2
*
SLC4A3
*
SLC4A4
*
SLC4A5
*
SLC4A7
*
SLC4A8
Electroneutral sodium bicarbonate exchanger 1 is a protein that in humans is encoded by the ''SLC4A8'' gene.
See also
* Solute carrier family
* cotransporter
Interactions
SLC4A8 has been shown to interact with Sodium-hydrogen antiporter 3 r ...
*
SLC4A9
*
SLC4A10
*
SLC4A11
Sodium bicarbonate transporter-like protein 11 is a protein that in humans is encoded by the ''SLC4A11'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...
Anion exchanger 1
The human anion exchanger 1 (AE1 or
Band 3
Band 3 anion transport protein, also known as anion exchanger 1 (AE1) or band 3 or solute carrier family 4 member 1 (SLC4A1), is a protein that is encoded by the gene in humans.
Band 3 anion transport protein is a phylogenetically-preserved ...
) binds
carbonic anhydrase II (CAII) forming a "transport
metabolon" as CAII binding activates AE1 transport activity about 10 fold. AE1 is also activated by interaction with
glycophorin, which also functions to target it to the plasma membrane. The membrane-embedded C-terminal domains may each span the membrane 13-16 times. According to the model of Zhu et al. (2003), AE1 in humans spans the membrane 16 times, 13 times as α-helix, and three times (TMSs 10, 11 and 14) possibly as β-strands. AE1 preferentially catalyzes 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.
AE1 in human
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s 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 Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty ac ...
from one monolayer of the
phospholipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
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, the mere presence of TMSs enhances the rates of lipid flip-flop.
Structure
The crystal structure of AE1 (CTD) at 3.5 angstroms has been determined. 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 led to proposal of 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.
There are several crystal structures available for the AE1 protein i
RCSB(links are also available i
TCDB.
:AE1: , , , , , , , , , , , , , , , , ,
Other members
Renal
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
Na
+:HCO cotransporters have been found to be members of the AE family. They catalyze the reabsorption of HCO in the renal proximal tubule in an electrogenic process that is inhibited by typical
stilbene Stilbene may refer to one of the two stereoisomers of 1,2-diphenylethene:
* (''E'')-Stilbene (''trans'' isomer)
* (''Z'')-Stilbene (''cis'' isomer)
See also
* Stilbenoid
Stilbenoids are hydroxylated derivatives of stilbene. They have a C6– ...
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, but this model conflicts with the 14 TMS model proposed for AE1. The transmembrane topology of the human pancreatic electrogenic Na
+:HO transporter, NBC1, has been studied. A TMS topology with N- and C-termini in the cytoplasm has been suggested. An extracellular loop determines the stoichiometry of Na
+-HCO cotransporters.
In addition to the Na
+-independent anion exchangers (AE1-3) and the Na
+:HCO cotransporters (NBCs) (which may be either electroneutral or electrogenic), a Na
+-driven HCO/Cl
− exchanger (NCBE) has been sequenced and characterized. It transports Na
+ + HCO 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 HCO secretion in cystic fibrosis patients.
Anion exchangers 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).
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 HCO, I
−, Br
−, NO 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.
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.
Transport reactions
The physiologically relevant transport reaction catalyzed by anion exchangers of the AE family is:
:Cl
− (in) + HCO (out) ⇌ Cl
− (out) + HCO (in).
That for the Na
+:HCO3- cotransporters is:
:Na
+ (out) + nHCO (out) → Na
+ (in) + nHCO (in).
That for the Na
+/HCO:H
+/Cl
− exchanger is:
:Na
+ (out) + HCO (out) + H
+ (in) + Cl
− (in) ⇌ Na
+ (in) + HCO (in) + H
+ (out) + Cl
− (out).
That for the boron efflux protein of plants and yeast is:
:Boron (in) → Boron (out)
See also
*
Solute carrier family
*
Transporter Classification Database
References
{{Solute carrier family, bg, bg0
Protein families
Transmembrane transporters
Solute carrier family