Slc26a9 is inhibited by the R-region of the cystic fibrosis transmembrane conductance regulator via the STAS domain.
SLC26 proteins function as anion exchangers, channels, and sensors. Previous cellular studies have shown that Slc26a3 and Slc26a6 interact with the R-region of the cystic fibrosis transmembrane conductance regulator (CFTR), (R)CFTR, via the Slc26-STAS (sulfate transporter anti-sigma) domain, resulting in mutual transport activation. We recently showed that Slc26a9 has both nCl(-)-HCO(3)(-) exchanger and Cl(-) channel function. In this study, we show that the purified STAS domain of Slc26a9 (a9STAS) binds purified (R)CFTR. When Slc26a9 and (R)CFTR fragments are co-expressed in Xenopus oocytes, both Slc26a9-mediated nCl(-)-HCO(3)(-) exchange and Cl(-) currents are almost fully inhibited. Deletion of the Slc26a9 STAS domain (a9-DeltaSTAS) virtually eliminated the Cl(-) currents with only a modest affect on nCl(-)-HCO(3)(-) exchange activity. Co-expression of a9-DeltaSTAS and the (R)CFTR fragment did not alter the residual a9-DeltaSTAS function. Replacing the Slc26a9 STAS domain with the Slc26a6 STAS domain (a6-a9-a6) does not change Slc26a9 function and is no longer inhibited by (R)CFTR. These data indicate that the Slc26a9-STAS domain, like other Slc26-STAS domains, binds CFTR in the R-region. However, unlike previously reported data, this binding interaction inhibits Slc26a9 ion transport activity. These results imply that Slc26-STAS domains may all interact with (R)CFTR but that the physiological outcome is specific to differing Slc26 proteins, allowing for dynamic and acute fine tuning of ion transport for various epithelia.
Chang
Min-Hwang
MH
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
Plata
Consuelo
C
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City 14000, Mexico.
Sindic
Aleksandra
A
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
Ranatunga
Wasantha K
WK
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
Chen
An-Ping
AP
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
Zandi-Nejad
Kambiz
K
Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Chan
Kim W
KW
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106.
Thompson
James
J
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
Mount
David B
DB
Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115; Renal Division, Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts 02132.
Romero
Michael F
MF
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106; Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905. Electronic address: romero.michael@mayo.edu.
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000076988:Sulfate Transporters; D014982:Xenopus laevis
D017920:Antiporters; D001639:Bicarbonates; D002712:Chlorides; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator