Novel Topology in C-terminal Region of the Human Plasma Membrane Anion Exchanger, AE1

Zhu, Qing; Lee, Diana W.K.; Casey, Joseph R.

doi:10.1074/jbc.m207797200

Cited by 139 publications

(188 citation statements)

References 48 publications

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“…This glycine at position 609 is conserved among all known vertebrate AE1 gene family sequences, providing an idea of functional importance of this residue. Gly-609 is predicted to lie within the seventh transmembrane domain of the polytopic AE1 protein, toward its cytoplasmic end (29). Gly-609 is also located close to two residues where missense mutations have been reported, in codons Arg-589 and Ser-613, reinforcing the importance of this region of the multiple transmembrane-spanning half of the molecule.…”

Section: Discussionmentioning

confidence: 99%

A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells

Rungroj

Devonald

Cuthbert

et al. 2004

Journal of Biological Chemistry

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Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. In this study we report a novel missense mutation, G609R, causing dominant dRTA in affected members of a large Caucasian pedigree who all exhibited metabolic acidosis with alkaline urine, prominent nephrocalcinosis, and progressive renal impairment. To investigate the potential disease mechanism, the consequent effects of this mutation were determined. We first assessed anion transport function of G609R by expression in Xenopus oocytes. Western blotting and immunofluorescence demonstrated that the mutant protein was expressed at the oocyte cell surface. Measuring chloride and bicarbonate fluxes revealed normal 4,4-diisothiocyanostilbene-2,2-disulfonic acidinhibitable anion exchange, suggesting that loss-offunction of kAE1 cannot explain the severe disease phenotype in this kindred. We next expressed epitopetagged wild-type or mutant kAE1 in Madin-Darby canine kidney cells. In monolayers grown to polarity, mutant kAE1 was detected subapically and at the apical membrane, as well as at the basolateral membrane, in contrast to the normal basolateral appearance of wildtype kAE1. These findings suggest that the seventh transmembrane domain that contains Gly-609 plays an important role in targeting kAE1 to the correct cell surface compartment. They confirm that dominant dRTA is associated with non-polarized trafficking of the protein, with no significant effect on anion transport function in vitro, which remains an unusual mechanism of human disease.

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Section: Discussionmentioning

confidence: 99%

A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells

Rungroj

Devonald

Cuthbert

et al. 2004

Journal of Biological Chemistry

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“…However, mutation of a CA2 binding site changed apparent transport stoichiometry (calculated from trans-monolayer short circuit currents) rather than abolishing HCO 3 Ϫ transport (21). Importance of the kAE1 C-terminal Tail to Plasmalemmal Anion Transport, and an Enlarged Functional Definition of the "Core CA2 Binding Site" of AE1-Recent cysteine accessibility scan evidence suggests that the human eAE1C-terminal cytoplasmic tail may extend from the terminal aa 911 as far as aa 872 (56). We previously reported that mouse eAE1 L890X (corresponding to human eAE1 L872X) exhibited loss-of-function in Xenopus oocytes, secondary to its intracellular retention (11).…”

Section: Interprotomeric Rescue Of Ae1-mediated Hcomentioning

confidence: 99%

Deficient HCO3- Transport in an AE1 Mutant with Normal Cl- Transport Can be Rescued by Carbonic Anhydrase II Presented on an Adjacent AE1 Protomer

Dahl¹,

Jiang

Chernova

et al. 2003

Journal of Biological Chemistry

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؊ exchange by an AE1 missense mutant devoid of CA2 binding, with activity further enhanced by CA2 co-expression. The same transport-incompetent AE1 mutants failed to rescue Cl ؊ /HCO 3 ؊ exchange by the AE1 truncation mutant 896X, despite preservation of the latter's core CA2 binding site. These data increase the minimal extent of a functionally defined CA2 binding site in AE1. The inter-protomeric rescue of HCO 3 ؊ transport within the AE1 dimer shows functional proximity of the C-terminal cytoplasmic tail of one protomer to the anion translocation pathway in the adjacent protomer within the AE1 heterodimer. The data strongly support the hypothesis that an intact transbilayer anion translocation pathway is completely contained within an AE1 monomer.

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“…Structure Figure 9 is a model of the topology of NBCe1-A, based on studies of the Cl-HCO 3 exchanger AE1 (86). All members of the family have a large cytoplasmic N terminus (Nt) and a much smaller cytoplasmic C terminus (Ct).…”

Section: Other Members Of the Slc4 Familymentioning

confidence: 99%

Acid-Base Transport by the Renal Proximal Tubule

Boron

2006

Journal of the American Society of Nephrology

170

144

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One of the major tasks of the renal proximal tubule is to secrete acid into the tubule lumen, thereby reabsorbing approximately 80% of the filtered HCO 3 ؊ as well as generating new HCO 3 ؊ for regulating blood pH. This review summarizes the cellular and molecular events that underlie four major processes in HCO 3 ؊ reabsorption. The first is CO 2 entry across the apical membrane, which in large part occurs via a gas channel (aquaporin 1) and acidifies the cell. The second process is apical H ؉ secretion via Na-H exchange and H ؉ pumping, processes that can be studied using the NH 4 ؉ prepulse technique. The third process is the basolateral exit of HCO 3 ؊ via the electrogenic Na/HCO 3 co-transporter, which is the subject of at least 10 mutations that cause severe proximal renal tubule acidosis in humans. The final process is the regulation of overall HCO 3 ؊ reabsorption by CO 2 and HCO 3 ؊ sensors at the basolateral membrane. Together, these processes ensure that the proximal tubule responds appropriately to acute acid-base disturbances and thereby contributes to the regulation of blood pH.

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Novel Topology in C-terminal Region of the Human Plasma Membrane Anion Exchanger, AE1

Cited by 139 publications

References 48 publications

A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells

A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells

Deficient HCO3- Transport in an AE1 Mutant with Normal Cl- Transport Can be Rescued by Carbonic Anhydrase II Presented on an Adjacent AE1 Protomer

Acid-Base Transport by the Renal Proximal Tubule

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