Crystal structures reveal the molecular basis of ion translocation in sodium/proton antiporters

Coincon, M.; Uzdavinys, Povilas; Nji, Emmanuel; Dotson, David; Winkelmann, Iven; Abdul-Hussein, Saba; Cameron, Alexander D.; Beckstein, Oliver; Drew, David

doi:10.1038/nsmb.3164

Cited by 88 publications

(138 citation statements)

References 63 publications

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“…This change is not as large as the 18 Å observed in the trimeric elevator transporter Gltph (40), or the 15 Å in the model of transport by VcINDY (41). Rather, a 10-Å change compares more with the 10-Å vertical displacement observed in the sodium/proton dimeric exchanger NapA, which is also proposed to function as an elevator transporter (42). Thus, the available evidence suggests that the SLC4, SLC26, and NAT family transporters all share a conserved elevator transport mechanism.…”

Section: Discussionmentioning

confidence: 74%

Structure of Bor1 supports an elevator transport mechanism for SLC4 anion exchangers

Thurtle‐Schmidt

Stroud

2016

Proc. Natl. Acad. Sci. U.S.A.

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Boron is essential for plant growth because of its incorporation into plant cell walls; however, in excess it is toxic to plants. Boron transport and homeostasis in plants is regulated in part by the borate efflux transporter Bor1, a member of the solute carrier (SLC) 4 transporter family with homology to the human bicarbonate transporter Band 3. Here, we present the 4.1-Å resolution crystal structure of Arabidopsis thaliana Bor1. The structure displays a dimeric architecture in which dimerization is mediated by centralized Gate domains. Comparisons with a structure of Band 3 in an outward-open state reveal that the Core domains of Bor1 have rotated inwards to achieve an occluded state. Further structural comparisons with UapA, a xanthine transporter from the nucleobase-ascorbate transporter family, show that the downward pivoting of the Core domains relative to the Gate domains may access an inward-open state. These results suggest that the SLC4, SLC26, and nucleobase-ascorbate transporter families all share an elevator transport mechanism in which alternating access is provided by Core domains that carry substrates across a membrane.T he defining feature of transporters is the ability to carry specific molecules across a membrane. The solute carrier (SLC) group comprises a diverse array of transporters grouped into at least 52 families based on function and sequence homology (1). The SLC4 family is termed the bicarbonate transporters and is subdivided into sodium-coupled cotransporters and anion exchanger subclasses. The SLC4 anion exchangers transport ions in an electroneutral manner, most commonly transporting bicarbonate in exchange for chloride. In addition to bicarbonate transporters, the SLC4 transporters include borate efflux transporters, originally discovered in plants (2, 3). Boron is an essential plant micronutrient that is taken up from the soil and participates in the formation of esters found in plant cell walls. Specifically, borate diesters cross-link a primary cell wall component, pectic polysaccharide rhamnogalacturonan II (RG-II) and, thus, contribute to plant cell wall stability (4, 5). In excess levels, however, boron is toxic to plants. The regulation of boron by transporters is therefore important for plant viability and has implications for worldwide agriculture. Indeed, there are ongoing efforts to engineer plants that are tolerant of either high or low boron levels in soil (6-8). The transport and regulation of boron levels is regulated partly by Bor1, a boron exporter that loads xylem, such that boron is transported from roots to shoots and leaves (3). The precise chemical nature boron takes during transport is not known, but is commonly assumed to be borate, an anionic form of boric acid. Bor1 is active in plants under limiting borate conditions, but is degraded under high concentrations of borate to avoid accumulation of toxic boron levels in plant shoots (9). Although the transporter function and regulation of Bor1 in response to excess borate have been defined, the mechanism by w...

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Section: Discussionmentioning

confidence: 74%

Structure of Bor1 supports an elevator transport mechanism for SLC4 anion exchangers

Thurtle‐Schmidt

Stroud

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Molecular dynamics (MD) simulations of the NapA crystal structure were therefore performed to investigate potential Na + ion coordination (16). Similar to the binding mode seen in MD simulations of E. coli NhaA (11,16), conserved aspartic acids D157 and D156 as well as T126 were seen to coordinate Na + in the middle of the discontinuous helix crossover ( Fig.…”

Section: Converting Electrogenic Napa Into An Electroneutral Transpormentioning

confidence: 79%

“…The simplest interpretation is that the different pH activity profiles reflect the 10-fold lower apparent affinities for Na + compared with Li + (11,13,16). As such, in NapA, protons could be more effective at competing for the binding of Na + than for Li + .…”

Section: Ph-dependent Activity Is An Intrinsic Property Of the Ion Bimentioning

confidence: 99%

“…However, it was still not possible to unambiguously identify a bound Na + ion in the electron density maps at the proposed ion binding site (16). Molecular dynamics (MD) simulations of the NapA crystal structure were therefore performed to investigate potential Na + ion coordination (16).…”

Section: Converting Electrogenic Napa Into An Electroneutral Transpormentioning

confidence: 99%

“…2A, Lower). However, unlike NhaA, where Na + binding in MD simulations was also seen to favor breakage of the salt bridge between D163 and K300 residues (12), in NapA, the equivalent salt bridge between K305 and D156 residues always remained intact, even upon Na + binding (16). This discrepancy may reflect the parameters used to model ion binding in the MD simulations or structural differences between the two proteins.…”

Section: Converting Electrogenic Napa Into An Electroneutral Transpormentioning

confidence: 99%

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Dissecting the proton transport pathway in electrogenic Na ⁺ /H ⁺ antiporters

Uzdavinys

Coincon

Nji

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sodium/proton exchangers of the SLC9 family mediate the transport of protons in exchange for sodium to help regulate intracellular pH, sodium levels, and cell volume. In electrogenic Na + + + /H + + + antiporters, it has been assumed that two ion-binding aspartate residues transport the two protons that are later exchanged for one sodium ion. However, here we show that we can switch the antiport activity of the bacterial Na + + + /H + + + antiporter NapA from being electrogenic to electroneutral by the mutation of a single lysine residue (K305). Electroneutral lysine mutants show similar ion affinities when driven by ∆pH, but no longer respond to either an electrochemical potential (Ψ) or could generate one when driven by ion gradients. We further show that the exchange activity of the human Na + + + /H + + + exchanger NHA2 (SLC9B2) is electroneutral, despite harboring the two conserved aspartic acid residues found in NapA and other bacterial homologues. Consistently, the equivalent residue to K305 in human NHA2 has been replaced with arginine, which is a mutation that makes NapA electroneutral. We conclude that a transmembrane embedded lysine residue is essential for electrogenic transport in Na + + + /H + + + antiporters.secondary active transporters | proton transport | membrane protein | Na + /H + exchangers | energetics

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A scenario for the origin of life: Volume regulation by bacteriorhodopsin required extremely voltage sensitive Na‐channels and very selective K‐channels

Naranjo

2022

BioEssays

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The osmotic activity produced by internal, non-permeable, anionic nucleic acids and metabolites causes a persistent and life-threatening cell swelling, or cellular edema, produced by the Gibbs-Donnan effect. This evolutionary-critical osmotic challenge must have been resolved by LUCA or its ancestors, but we lack a cell-physiology look into the biophysical constraints to the solutions. Like mycoplasma, early cells conceivably preserved their volume with Cl − , Na + , and K + -channels, Na + /H + -exchangers, and a light-dependent bacteriorhodopsin-like H + -pump. Here, I simulated protocells having these ionic-permeabilities and inhabiting an oceanic pond before the Great-Oxygenation-Event. Protocells showed better volume control and stable resting potentials at lower external pH and higher temperatures, favoring a certain type of extremophile life. Prevention of Na + -influx at night, with low bacteriorhodopsin activity, required deep shutdown of highly voltage-sensitive Na + -channels and extremely selective K + -channels, two conserved features essential for modern neuronal encoding. The Gibbs-Donnan effect universality implies that extraterrestrial cells, if they exist, may reveal similar volume-controlling mechanisms.

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Crystal structures reveal the molecular basis of ion translocation in sodium/proton antiporters

Cited by 88 publications

References 63 publications

Structure of Bor1 supports an elevator transport mechanism for SLC4 anion exchangers

Structure of Bor1 supports an elevator transport mechanism for SLC4 anion exchangers

Dissecting the proton transport pathway in electrogenic Na ⁺ /H ⁺ antiporters

A scenario for the origin of life: Volume regulation by bacteriorhodopsin required extremely voltage sensitive Na‐channels and very selective K‐channels

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Crystal structures reveal the molecular basis of ion translocation in sodium/proton antiporters

Cited by 88 publications

References 63 publications

Structure of Bor1 supports an elevator transport mechanism for SLC4 anion exchangers

Structure of Bor1 supports an elevator transport mechanism for SLC4 anion exchangers

Dissecting the proton transport pathway in electrogenic Na + /H + antiporters

A scenario for the origin of life: Volume regulation by bacteriorhodopsin required extremely voltage sensitive Na‐channels and very selective K‐channels

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Dissecting the proton transport pathway in electrogenic Na ⁺ /H ⁺ antiporters