Anion Exchange Protein in Southeast Asian Ovalocytes: Heterodimer Formation between Normal and Variant Subunits

Jennings, Michael L.; Gosselink, Peter G.

doi:10.1021/bi00011a013

Cited by 41 publications

(37 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because AE1 SAO fails to bind stilbenes either in red cells (35) or as solubilized protein (44), the sensitivity of the rescued Cl Ϫ / HCO 3 Ϫ activity to DIDS allows attribution of transport function within the heterodimer uniquely to the LDAAA protomer. This result strongly supports the hypothesis, suggested by anion transport measurements in SAO red cells (45,46), that an AE1 monomer suffices to constitute an intact anion permeability pathway.…”

Section: Functional Effects Of Sequential Truncation Of the Kae1 C-supporting

confidence: 90%

“…This conclusion assumes that AE1 mutant polypeptide homodimers and heterodimers exhibit equivalent surface expression and equivalent intersubunit interaction constants. The apparent ability of SAO maximally to rescue Cl Ϫ /HCO 3 Ϫ exchange by kAE1 LDAAA is consistent with data showing that AE1 SAO within a heterodimer does not decrease equilibrium sulfate/sulfate exchange at pH 7.0 by the wt eAE1 polypeptide component of (heterozygous) Southeast Asian ovalocytes (45). However, initial rates of non-saturating sulfate influx at pH 6.0 (35) or of an index of equilibrium Cl Ϫ /Cl Ϫ exchange in SAO red cells (46) were reported to be ϳ25% lower than those in normal red cells.…”

Section: Interprotomeric Rescue Of Ae1-mediated Hcosupporting

confidence: 88%

“…Furthermore, the LDAAA protomer of the heterodimer suffices to constitute a transbilayer anion translocation pathway. The hyperbolic concentration dependence of AE1-mediated Cl Ϫ transport (5,6,48), and the properties of DIDS-sensitive sulfate transport and stilbene binding in SAO red cells (35,45,46) have long suggested that the transbilayer anion translocation pathway of dimeric AE1 is contained within an AE1 monomer. 4 The rescued activity Cl Ϫ /HCO 3 Ϫ exchange activity shown in Fig.…”

Section: Interprotomeric Rescue Of Ae1-mediated Hcomentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

؊ 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.

show abstract

Section: Functional Effects Of Sequential Truncation Of the Kae1 C-supporting

confidence: 90%

Section: Interprotomeric Rescue Of Ae1-mediated Hcosupporting

confidence: 88%

Section: Interprotomeric Rescue Of Ae1-mediated Hcomentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…In contrast, kAE1 could traffic to the plasma membrane after forming hetero-oligomers with the recessive kAE1 S773P and G701D mutants. This is similar to AE1 SAO, a mutant that forms heterodimers with the normal protein that are present at the red cell surface (54). The normal AE1 protein retains transport function, although it is associated with an inactive SAO subunit (28).…”

Section: Discussionmentioning

confidence: 79%

Trafficking Defects of a Novel Autosomal Recessive Distal Renal Tubular Acidosis Mutant (S773P) of the Human Kidney Anion Exchanger (kAE1)

Kittanakom

Cordat

Akkarapatumwong

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Autosomal dominant and recessive distal renal tubular acidosis (dRTA) can be caused by mutations in the anion exchanger 1 (AE1 or SLC4A1) gene, which encodes the erythroid chloride/bicarbonate anion exchanger membrane glycoprotein (eAE1) and a truncated kidney isoform (kAE1). The biosynthesis and trafficking of kAE1 containing a novel recessive missense dRTA mutation (kAE1 S773P) was studied in transiently transfected HEK-293 cells, expressing the mutant alone or in combination with wild-type kAE1 or another recessive mutant, kAE1 G701D. The kAE1 S773P mutant was expressed at a three times lower level than wild-type, had a 2-fold decrease in its half-life, and was targeted for degradation by the proteasome. It could not be detected at the plasma membrane in human embryonic kidney cells and showed predominant endoplasmic reticulum immunolocalization in both human embryonic kidney and LLC-PK1 cells. The oligosaccharide on a kAE1 S773P N-glycosylation mutant (N555) was not processed to the complex form indicating impaired exit from the endoplasmic reticulum. The kAE1 S773P mutant showed decreased binding to an inhibitor affinity resin and increased sensitivity to proteases, suggesting that it was not properly folded. The other recessive dRTA mutant, kAE1 G701D, also exhibited defective trafficking to the plasma membrane. The recessive kAE1 mutants formed dimers like wild-type AE1 and could hetero-oligomerize with wild-type kAE1 or with each other. Hetero-oligomers of wild-type kAE1 with recessive kAE1 S773P or G701D, in contrast to the dominant kAE1 R589H mutant, were delivered to the plasma membrane.

show abstract

“…Homozygotes have not been found, and are presumed to be embryonic lethal. The stable mutant polypeptide is present at normal abundance in the membrane, where it heterodimerizes at apparent normal affinity with wild-type polypeptide (Jennings and Gosselink, 1995 (Dahl et al, 2003), the minimal impact of its dominant effects upon the wild-type monomer within the SAO/wt heterodimer Kuma et al, 2002) explain its lack of renal phenotype. Heterozygote red cell membranes exhibit increased rigidity and cold-induced cation permeability, and the allele seems to confer protection against cerebral complications of malaria.…”

Section: Eae1 Erythroid Disease Phenotypesmentioning

confidence: 99%

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Alper

2009

Journal of Experimental Biology

194

220

View full text Add to dashboard Cite

SUMMARY Plasmalemmal Cl–/HCO3–exchangers are encoded by the SLC4 and SLC26 gene superfamilies, and function to regulate intracellular pH,[Cl–] and cell volume. The Cl–/HCO3– exchangers of polarized epithelial cells also contribute to transepithelial secretion and reabsorption of acid–base equivalents and Cl–. This review focuses on Na+-independent electroneutral Cl–/HCO3– exchangers of the SLC4 family. Human SLC4A1/AE1 mutations cause the familial erythroid disorders of spherocytic anemia, stomatocytic anemia and ovalocytosis. A largely discrete set of AE1 mutations causes familial distal renal tubular acidosis. The Slc4a2/Ae2–/– mouse dies before weaning with achlorhydria and osteopetrosis. A hypomorphic Ae2–/– mouse survives to exhibit male infertility with defective spermatogenesis and a syndrome resembling primary biliary cirrhosis. A human SLC4A3/AE3 polymorphism is associated with seizure disorder, and the Ae3–/– mouse has increased seizure susceptibility. The transport mechanism of mammalian SLC4/AE polypeptides is that of electroneutral Cl–/anion exchange,but trout erythroid Ae1 also mediates Cl– conductance. Erythroid Ae1 may mediate the DIDS-sensitive Cl– conductance of mammalian erythrocytes, and, with a single missense mutation, can mediate electrogenic SO42–/Cl– exchange. AE1 trafficking in polarized cells is regulated by phosphorylation and by interaction with other proteins. AE2 exhibits isoform-specific patterns of acute inhibition by acidic intracellular pH and independently by acidic extracellular pH. In contrast, AE2 is activated by hypertonicity and, in a pH-independent manner, by ammonium and by hypertonicity. A growing body of structure–function and interaction data, together with emerging information about physiological function and structure, is advancing our understanding of SLC4 anion exchangers.

show abstract

Anion Exchange Protein in Southeast Asian Ovalocytes: Heterodimer Formation between Normal and Variant Subunits

Cited by 41 publications

References 55 publications

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

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

Trafficking Defects of a Novel Autosomal Recessive Distal Renal Tubular Acidosis Mutant (S773P) of the Human Kidney Anion Exchanger (kAE1)

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Contact Info

Product

Resources

About