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Aquaporins with anion/monocarboxylate permeability: mechanisms, relevance for pathogen-host interactions.

Rambow J, Wu B, Rönfeldt D, Beitz E - Front Pharmacol (2014)

Bottom Line: It became apparent that not all aquaporins clearly fit into one of only two subfamilies.Here, we summarize the findings on aquaporin anion transport, analyze the pore layout of such aquaporins in comparison to prototypical non-selective anion channels, monocarboxylate transporters, and formate-nitrite transporters.Finally, we discuss in which scenarios anion conducting aquaporins may be of physiological relevance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel Kiel, Germany.

ABSTRACT
Classically, aquaporins are divided based on pore selectivity into water specific, orthodox aquaporins and solute-facilitating aquaglyceroporins, which conduct, e.g., glycerol and urea. However, more aquaporin-passing substrates have been identified over the years, such as the gasses ammonia and carbon dioxide or the water-related hydrogen peroxide. It became apparent that not all aquaporins clearly fit into one of only two subfamilies. Furthermore, certain aquaporins from both major subfamilies have been reported to conduct inorganic anions, such as chloride, or monoacids/monocarboxylates, such as lactic acid/lactate. Here, we summarize the findings on aquaporin anion transport, analyze the pore layout of such aquaporins in comparison to prototypical non-selective anion channels, monocarboxylate transporters, and formate-nitrite transporters. Finally, we discuss in which scenarios anion conducting aquaporins may be of physiological relevance.

No MeSH data available.


Related in: MedlinePlus

Topology and sequence comparison of selected AQPs. Red shading highlights residues of the ar/R selectivity filter, blue the NPA regions. Glycines of helix contact points are colored in green, and the Leu51Arg mutation site in AQP5 in orange. The Thr63Ile and Lys72Glu mutations of AQP6 are colored magenta. Connecting loops are labeled A–E, and the transmembrane spanning helices TM1-6. The termini and the connecting loop C are excluded from the sequence alignment. Blue bullets below the sequences mark residues of the AQP channel lining. The sequences are grouped according to their subfamily attribution, i.e., the water specific type (AQP1, AQP6, AQP5) and aquaglyceroporins (Escherichia coli GlpF, human AQP9, NIP2;1, LpGlpF1 and LpGlpF4, SmAQP).
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Figure 2: Topology and sequence comparison of selected AQPs. Red shading highlights residues of the ar/R selectivity filter, blue the NPA regions. Glycines of helix contact points are colored in green, and the Leu51Arg mutation site in AQP5 in orange. The Thr63Ile and Lys72Glu mutations of AQP6 are colored magenta. Connecting loops are labeled A–E, and the transmembrane spanning helices TM1-6. The termini and the connecting loop C are excluded from the sequence alignment. Blue bullets below the sequences mark residues of the AQP channel lining. The sequences are grouped according to their subfamily attribution, i.e., the water specific type (AQP1, AQP6, AQP5) and aquaglyceroporins (Escherichia coli GlpF, human AQP9, NIP2;1, LpGlpF1 and LpGlpF4, SmAQP).

Mentions: AQP6 has a preference for nitrate, yet halide anions are channeled as well yielding the permeability sequence: NO3- > I- ≫ Br- > Cl- ≫ F- (Ikeda et al., 2002). The passage of anions was shown not to occur via the central pore but through the individual pores of the protomers raising the question about peculiarities in the AQP6 pore layout. Reversal of the positive charge of a lysine residue, Lys72, positioned at the cytoplasmic pore mouth by mutational replacement with a negatively charged glutamate (Figure 2) hardly affected anion conductance (Yasui et al., 1999). Two hydroxyl-containing residues, i.e., a tyrosine, Tyr37, and a threonine, Thr63, within the AQP6 channel path were proposed to be situated in juxtaposition to the two asparagines of the NPA motive acting as a fourfold anion coordination site. Indeed, mutation of Thr63 to isoleucine reduced nitrate permeability (Ikeda et al., 2002). Full elimination of AQP6 anion permeability and, at the same time, a gain of high water permeability was eventually achieved by replacement of an asparagine residue, Asn60, located at the junction of transmembrane helices 2 and 5 by glycine (Liu et al., 2005). Contact points of transmembrane helices in AQPs and in other membrane proteins typically contain glycines, which form dents in the interacting helix surfaces locking them in place (Murata et al., 2000). As a consequence, the transmembrane domains are less prone to slipping movements against each other leading to an overall more rigid protein structure. Rigidity is important to keep the 20 Å long AQP channel with a narrow diameter of 3–4 Å open for the efficient and continuous passage of water. It is speculated that the unique Asn60 at an AQP-typical glycine position induces exactly that degree of helix slipping in AQP6 to allow anions, such as nitrate and (partially) hydrated halides, which are consequently larger than a water molecule, to enter and pass the channel (Liu et al., 2005). A recent, serendipitous finding obtained with an AQP5 mutant seems to confirm this interpretation (Qin and Boron, 2013). AQP5 is typically found in type 1 pneumocytes and salivary glands. Actually aiming at modifying the lining of the central pore of AQP5 to study gas transport properties, a leucine, Leu51, was changed to arginine. One striking effect, however, was induction of anion permeability of the four individual pores of the AQP5-Leu51Arg mutant with a permeation sequence equal to AQP6. The mutation site is not within the channel itself but lies right next to the glycine–glycine contact point of transmembrane helices 2 and 5 of AQP5 and, thus, in the very same region as Asn60 in AQP6 (Figure 2).


Aquaporins with anion/monocarboxylate permeability: mechanisms, relevance for pathogen-host interactions.

Rambow J, Wu B, Rönfeldt D, Beitz E - Front Pharmacol (2014)

Topology and sequence comparison of selected AQPs. Red shading highlights residues of the ar/R selectivity filter, blue the NPA regions. Glycines of helix contact points are colored in green, and the Leu51Arg mutation site in AQP5 in orange. The Thr63Ile and Lys72Glu mutations of AQP6 are colored magenta. Connecting loops are labeled A–E, and the transmembrane spanning helices TM1-6. The termini and the connecting loop C are excluded from the sequence alignment. Blue bullets below the sequences mark residues of the AQP channel lining. The sequences are grouped according to their subfamily attribution, i.e., the water specific type (AQP1, AQP6, AQP5) and aquaglyceroporins (Escherichia coli GlpF, human AQP9, NIP2;1, LpGlpF1 and LpGlpF4, SmAQP).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150397&req=5

Figure 2: Topology and sequence comparison of selected AQPs. Red shading highlights residues of the ar/R selectivity filter, blue the NPA regions. Glycines of helix contact points are colored in green, and the Leu51Arg mutation site in AQP5 in orange. The Thr63Ile and Lys72Glu mutations of AQP6 are colored magenta. Connecting loops are labeled A–E, and the transmembrane spanning helices TM1-6. The termini and the connecting loop C are excluded from the sequence alignment. Blue bullets below the sequences mark residues of the AQP channel lining. The sequences are grouped according to their subfamily attribution, i.e., the water specific type (AQP1, AQP6, AQP5) and aquaglyceroporins (Escherichia coli GlpF, human AQP9, NIP2;1, LpGlpF1 and LpGlpF4, SmAQP).
Mentions: AQP6 has a preference for nitrate, yet halide anions are channeled as well yielding the permeability sequence: NO3- > I- ≫ Br- > Cl- ≫ F- (Ikeda et al., 2002). The passage of anions was shown not to occur via the central pore but through the individual pores of the protomers raising the question about peculiarities in the AQP6 pore layout. Reversal of the positive charge of a lysine residue, Lys72, positioned at the cytoplasmic pore mouth by mutational replacement with a negatively charged glutamate (Figure 2) hardly affected anion conductance (Yasui et al., 1999). Two hydroxyl-containing residues, i.e., a tyrosine, Tyr37, and a threonine, Thr63, within the AQP6 channel path were proposed to be situated in juxtaposition to the two asparagines of the NPA motive acting as a fourfold anion coordination site. Indeed, mutation of Thr63 to isoleucine reduced nitrate permeability (Ikeda et al., 2002). Full elimination of AQP6 anion permeability and, at the same time, a gain of high water permeability was eventually achieved by replacement of an asparagine residue, Asn60, located at the junction of transmembrane helices 2 and 5 by glycine (Liu et al., 2005). Contact points of transmembrane helices in AQPs and in other membrane proteins typically contain glycines, which form dents in the interacting helix surfaces locking them in place (Murata et al., 2000). As a consequence, the transmembrane domains are less prone to slipping movements against each other leading to an overall more rigid protein structure. Rigidity is important to keep the 20 Å long AQP channel with a narrow diameter of 3–4 Å open for the efficient and continuous passage of water. It is speculated that the unique Asn60 at an AQP-typical glycine position induces exactly that degree of helix slipping in AQP6 to allow anions, such as nitrate and (partially) hydrated halides, which are consequently larger than a water molecule, to enter and pass the channel (Liu et al., 2005). A recent, serendipitous finding obtained with an AQP5 mutant seems to confirm this interpretation (Qin and Boron, 2013). AQP5 is typically found in type 1 pneumocytes and salivary glands. Actually aiming at modifying the lining of the central pore of AQP5 to study gas transport properties, a leucine, Leu51, was changed to arginine. One striking effect, however, was induction of anion permeability of the four individual pores of the AQP5-Leu51Arg mutant with a permeation sequence equal to AQP6. The mutation site is not within the channel itself but lies right next to the glycine–glycine contact point of transmembrane helices 2 and 5 of AQP5 and, thus, in the very same region as Asn60 in AQP6 (Figure 2).

Bottom Line: It became apparent that not all aquaporins clearly fit into one of only two subfamilies.Here, we summarize the findings on aquaporin anion transport, analyze the pore layout of such aquaporins in comparison to prototypical non-selective anion channels, monocarboxylate transporters, and formate-nitrite transporters.Finally, we discuss in which scenarios anion conducting aquaporins may be of physiological relevance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel Kiel, Germany.

ABSTRACT
Classically, aquaporins are divided based on pore selectivity into water specific, orthodox aquaporins and solute-facilitating aquaglyceroporins, which conduct, e.g., glycerol and urea. However, more aquaporin-passing substrates have been identified over the years, such as the gasses ammonia and carbon dioxide or the water-related hydrogen peroxide. It became apparent that not all aquaporins clearly fit into one of only two subfamilies. Furthermore, certain aquaporins from both major subfamilies have been reported to conduct inorganic anions, such as chloride, or monoacids/monocarboxylates, such as lactic acid/lactate. Here, we summarize the findings on aquaporin anion transport, analyze the pore layout of such aquaporins in comparison to prototypical non-selective anion channels, monocarboxylate transporters, and formate-nitrite transporters. Finally, we discuss in which scenarios anion conducting aquaporins may be of physiological relevance.

No MeSH data available.


Related in: MedlinePlus