Modular structure of sodium-coupled bicarbonate transporters

Boron, Walter F.; Chen, Li Ming; Parker, Mark D.

doi:10.1242/jeb.028563

Cited by 132 publications

(184 citation statements)

References 116 publications

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“…1D), and although the BBS should also allow targeting sAC with specific drugs, it appears to be too small for typical drug-like molecules. In an attempt to identify a pharmacological approach to exploit the sAC BBS, we therefore tested 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), which has effects on cellular HCO 3 − /pH systems normally attributed to inhibition of bicarbonate transporters (40). We speculated that DIDS's sulfonates might mimic HCO 3 − and allow inhibitory binding to BBS and additional regulatory site regions.…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

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

123

215

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cAMP is an evolutionary conserved, prototypic second messenger regulating numerous cellular functions. In mammals, cAMP is synthesized by one of 10 homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3−); it thereby serves as a cellular sensor for HCO3−, carbon dioxide (CO2), and pH in physiological functions, such as sperm activation, aqueous humor formation, and metabolic regulation. Here, we describe crystal structures of human sAC catalytic domains in the apo state and in complex with substrate analog, products, and regulators. The activator HCO3− binds adjacent to Arg176, which acts as a switch that enables formation of the catalytic cation sites. An anionic inhibitor, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, inhibits sAC through binding to the active site entrance, which blocks HCO3− activation through steric hindrance and trapping of the Arg176 side chain. Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3− sensing and a basis for targeting this system with drugs.

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Section: Resultsmentioning

confidence: 99%

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

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

123

215

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“…The electrogenic Na ϩ -HCO 3 Ϫ cotransporter 1 (NBCe1-A) 2 is responsible for reabsorbing 60 -80% of the filtered HCO 3 Ϫ load in the mammalian kidney. NBCe1-A belongs to the SLC4 HCO 3 Ϫ transporter family that contains several HCO 3 Ϫ -coupled transporters including Na ϩ -independent Cl Ϫ /HCO 3 Ϫ exchangers, Na ϩ -HCO 3 Ϫ cotransporters (electrogenic and electroneutral), and a Na ϩ -driven Cl Ϫ /HCO 3 Ϫ exchanger (1-3).…”

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confidence: 99%

“…NBCe1-A is expressed in the kidney and eye, NBCe1-B is expressed in pancreas, duodenum, colon, and several other tissues, and NBCe1-C is predominantly expressed in the brain. NBCe1-A differs from NBCe1-B/NBCe1-C in the N-terminal initial 85 amino acids, and NBCe1-C differs from NBCe1-A/ NBCe1-B in the 61 C-terminal amino acids (1)(2)(3).…”

mentioning

confidence: 99%

“…In particular, residue Thr 442 in TM 1 was proposed to form an external gate for the transported substrates (5). Interestingly, substitution of Asp 555 to glutamic acid in the proposed TM 5 of NBCe1-A induced an outward rectifying Cl Ϫ current and altered the transport substrate selectivity, indicating it plays an important role in HCO 3 Ϫ selectivity (7). Notably, this residue is in close proximity of the proposed DIDS (a functional inhibitor) binding site of NBCe1-A (Lys 559 ) (8).…”

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confidence: 99%

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Topological Location and Structural Importance of the NBCe1-A Residues Mutated in Proximal Renal Tubular Acidosis

Zhu

Kao

Azimov

et al. 2010

Journal of Biological Chemistry

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“…Another member of the AE 2.A.31 family, mammalian NaBC, functions as an electrogenic voltage-regulated and Na + -coupled borate anion transporter (Park et al, 2004), while YNL275w from S. cerevisiae transports HCO 3 2 , Cl 2 , I 2 , Br 2 , NO 3 2 , and borate anions (Zhao and Reithmeier, 2001;Jennings et al, 2007). Mechanistic explanations for some AE 2.A.31 family members have been offered (Boron et al, 2009), but it is not known if uniport, anion/anion (other than borate) antiport, or anion/cation symport account for permeation of ions through plant borate transporters.…”

Section: Introductionmentioning

confidence: 99%

A Barley Efflux Transporter Operates in a Na⁺-Dependent Manner, as Revealed by a Multidisciplinary Platform

et al. 2015

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Plant growth and survival depend upon the activity of membrane transporters that control the movement and distribution of solutes into, around, and out of plants. Although many plant transporters are known, their intrinsic properties make them difficult to study. In barley (Hordeum vulgare), the root anion-permeable transporter Bot1 plays a key role in tolerance to high soil boron, facilitating the efflux of borate from cells. However, its three-dimensional structure is unavailable and the molecular basis of its permeation function is unknown. Using an integrative platform of computational, biophysical, and biochemical tools as well as molecular biology, electrophysiology, and bioinformatics, we provide insight into the origin of transport function of Bot1. An atomistic model, supported by atomic force microscopy measurements, reveals that the protein folds into 13 transmembrane-spanning and five cytoplasmic a-helices. We predict a trimeric assembly of Bot1 and the presence of a Na + ion binding site, located in the proximity of a pore that conducts anions. Patch-clamp electrophysiology of Bot1 detects Na + -dependent polyvalent anion transport in a Nernstian manner with channel-like characteristics. Using alanine scanning, molecular dynamics simulations, and transport measurements, we show that conductance by Bot1 is abolished by removal of the Na + ion binding site. Our data enhance the understanding of the permeation functions of Bot1.

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Modular structure of sodium-coupled bicarbonate transporters

Cited by 132 publications

References 116 publications

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Topological Location and Structural Importance of the NBCe1-A Residues Mutated in Proximal Renal Tubular Acidosis

A Barley Efflux Transporter Operates in a Na⁺-Dependent Manner, as Revealed by a Multidisciplinary Platform

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Modular structure of sodium-coupled bicarbonate transporters

Cited by 132 publications

References 116 publications

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Topological Location and Structural Importance of the NBCe1-A Residues Mutated in Proximal Renal Tubular Acidosis

A Barley Efflux Transporter Operates in a Na+-Dependent Manner, as Revealed by a Multidisciplinary Platform

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Product

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A Barley Efflux Transporter Operates in a Na⁺-Dependent Manner, as Revealed by a Multidisciplinary Platform