Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Glaucoma, cataracts, and proximal renal tubular acidosis are diseases caused by point mutations in the human electrogenic Na(+) bicarbonate cotransporter (NBCe1/SLC4A4) (1, 2). One such mutation, R298S, is located in the cytoplasmic N-terminal domain of NBCe1 and has only moderate (75%) function. As SLC transporters have high similarity in their membrane and N-terminal primary sequences, we homology-modeled NBCe1 onto the crystal structure coordinates of Band 3(AE1) (3). Arg-298 is predicted to be located in a solvent-inaccessible subsurface pocket and to associate with Glu-91 or Glu-295 via H-bonding and charge-charge interactions. We perturbed these putative interactions between Glu-91 and Arg-298 by site-directed mutagenesis and used expression in Xenopus oocyte to test our structural model. Mutagenesis of either residue resulted in reduced transport function. Function was "repaired" by charge reversal (E91R/R298E), implying that these two residues are interchangeable and interdependent. These results contrast the current understanding of the AE1 N terminus as protein-binding sites and propose that hkNBCe1 (and other SLC4) cytoplasmic N termini play roles in controlling HCO(3)(-) permeation.
Alper,
Genetic diseases of acid-base transporters.
2002, Pubmed
Alper,
Genetic diseases of acid-base transporters.
2002,
Pubmed
Baron,
Zn2+ and H+ are coactivators of acid-sensing ion channels.
2001,
Pubmed
,
Xenbase
Biemesderfer,
NHE3: a Na+/H+ exchanger isoform of renal brush border.
1993,
Pubmed
Canutescu,
A graph-theory algorithm for rapid protein side-chain prediction.
2003,
Pubmed
Chernova,
Functional comparison of mouse slc26a6 anion exchanger with human SLC26A6 polypeptide variants: differences in anion selectivity, regulation, and electrogenicity.
2005,
Pubmed
,
Xenbase
Chernova,
Structure-function relationships of AE2 regulation by Ca(i)(2+)-sensitive stimulators NH(4+) and hypertonicity.
2003,
Pubmed
,
Xenbase
Cunningham,
Defective parathyroid hormone regulation of NHE3 activity and phosphate adaptation in cultured NHERF-1-/- renal proximal tubule cells.
2004,
Pubmed
Demirci,
Proximal renal tubular acidosis and ocular pathology: a novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1).
2006,
Pubmed
,
Xenbase
Dinour,
A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects.
2004,
Pubmed
,
Xenbase
Fakler,
Identification of a titratable lysine residue that determines sensitivity of kidney potassium channels (ROMK) to intracellular pH.
1996,
Pubmed
,
Xenbase
Gawenis,
Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na+/HCO3- cotransporter.
2007,
Pubmed
Gerchman,
Histidine-226 is part of the pH sensor of NhaA, a Na+/H+ antiporter in Escherichia coli.
1993,
Pubmed
Gill,
Preliminary X-ray diffraction analysis of the cytoplasmic N-terminal domain of the Na/HCO3 cotransporter NBCe1-A.
2006,
Pubmed
Gross,
The stoichiometry of the electrogenic sodium bicarbonate cotransporter pNBC1 in mouse pancreatic duct cells is 2 HCO(3)(-):1 Na(+).
2001,
Pubmed
Gross,
The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent.
2001,
Pubmed
Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed
Horita,
Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities.
2005,
Pubmed
,
Xenbase
Igarashi,
Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma.
2001,
Pubmed
Igarashi,
Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities.
1999,
Pubmed
Inatomi,
Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis.
2004,
Pubmed
,
Xenbase
Klingenberg,
Structure-function relationship in UCP1.
1999,
Pubmed
Laskowski,
Validation of protein models derived from experiment.
1998,
Pubmed
Lee,
Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
2005,
Pubmed
Margeta-Mitrovic,
A trafficking checkpoint controls GABA(B) receptor heterodimerization.
2000,
Pubmed
,
Xenbase
McAlear,
Electrogenic Na/HCO3 cotransporter (NBCe1) variants expressed in Xenopus oocytes: functional comparison and roles of the amino and carboxy termini.
2006,
Pubmed
,
Xenbase
Park,
NaBC1 is a ubiquitous electrogenic Na+ -coupled borate transporter essential for cellular boron homeostasis and cell growth and proliferation.
2004,
Pubmed
,
Xenbase
Rajan,
TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor.
2000,
Pubmed
,
Xenbase
Romero,
The SLC4 family of HCO 3 - transporters.
2004,
Pubmed
Romero,
Electrogenic Na+/HCO3- cotransporters: cloning and physiology.
1999,
Pubmed
Romero,
Molecular pathophysiology of SLC4 bicarbonate transporters.
2005,
Pubmed
Romero,
Cloning and functional expression of rNBC, an electrogenic Na(+)-HCO3- cotransporter from rat kidney.
1998,
Pubmed
,
Xenbase
Romero,
Expression cloning and characterization of a renal electrogenic Na+/HCO3- cotransporter.
1997,
Pubmed
,
Xenbase
Schultheis,
Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger.
1998,
Pubmed
Schwede,
SWISS-MODEL: An automated protein homology-modeling server.
2003,
Pubmed
Sciortino,
Cation and voltage dependence of rat kidney electrogenic Na(+)-HCO(-)(3) cotransporter, rkNBC, expressed in oocytes.
1999,
Pubmed
,
Xenbase
Shirakabe,
IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1).
2006,
Pubmed
,
Xenbase
Stewart,
Acute pH-dependent regulation of AE2-mediated anion exchange involves discrete local surfaces of the NH2-terminal cytoplasmic domain.
2004,
Pubmed
,
Xenbase
Stroffekova,
Identification of the pH sensor and activation by chemical modification of the ClC-2G Cl- channel.
1998,
Pubmed
,
Xenbase
Takano,
Arabidopsis boron transporter for xylem loading.
2002,
Pubmed
Tatishchev,
Identification of membrane topography of the electrogenic sodium bicarbonate cotransporter pNBC1 by in vitro transcription/translation.
2003,
Pubmed
Toye,
The human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia.
2006,
Pubmed
,
Xenbase
Vriend,
WHAT IF: a molecular modeling and drug design program.
1990,
Pubmed
Wang,
Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice.
1999,
Pubmed
Willard,
VADAR: a web server for quantitative evaluation of protein structure quality.
2003,
Pubmed
Yeh,
Mechanism and molecular determinant for regulation of rabbit transient receptor potential type 5 (TRPV5) channel by extracellular pH.
2003,
Pubmed
Yoo,
Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A.
2003,
Pubmed
,
Xenbase
Zerangue,
A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels.
1999,
Pubmed
,
Xenbase
Zhang,
Crystallographic structure and functional interpretation of the cytoplasmic domain of erythrocyte membrane band 3.
2000,
Pubmed
