biostudies-literatureChen APNational Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHS108145https://www.ebi.ac.uk/biostudies/studies/S-EPMC11834044biostudies-literatureUnknown301(2)The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic sulfate transporter and anti-sigma (STAS) domain and the R domain of cystic fibrosis (CF) transmembrane regulator. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in nonmammals. Despite the numerous studies involving the STAS domains in SLC26 proteins, the role of the disordered loop region has not been identified. Deletion of the entire Slc26a9-STAS domain results in loss of Cl^- channel function. Surprisingly, we found that partial or full deletion of the STAS-disordered loop substantially increases the SLC26A9 chloride transport-channel activity. BioinformaThe Journal of biological chemistryDisorder within order: Identification of the disordered loop of STAS domain as the inhibitory domain in SLC26A9 chloride channel.PMC11834044R25 DK101405Decker JWChen APChang MHHolmes HRomero MFfalseDisorder within order: Identification of the disordered loop of STAS domain as the inhibitory domain in SLC26A9 chloride channel.The chloride transporter-channel SLC26A9 is mediated by a reciprocal regulatory mechanism through the interaction between its cytoplasmic sulfate transporter and anti-sigma (STAS) domain and the R domain of cystic fibrosis (CF) transmembrane regulator. In vertebrate Slc26a9s, the STAS domain structures are interrupted by a disordered loop which is conserved in mammals but is variable in nonmammals. Despite the numerous studies involving the STAS domains in SLC26 proteins, the role of the disordered loop region has not been identified. Deletion of the entire Slc26a9-STAS domain results in loss of Cl^- channel function. Surprisingly, we found that partial or full deletion of the STAS-disordered loop substantially increases the SLC26A9 chloride transport-channel activity. Bioinforma2025-01-01T00:00:00Z2025 Feb2026-06-01T21:05:22.609Z2025-04-04T02:51:23.953ZS-EPMC118340443973216910.1016/j.jbc.2024.108145