期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 13, 页码 8711-8722出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M704328200
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资金
- NIDCR NIH HHS [DE 12309] Funding Source: Medline
- NIDDK NIH HHS [DK 38938, DK 49835] Funding Source: Medline
- NIGMS NIH HHS [GM 08203] Funding Source: Medline
Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 ( solute carrier 26 family member 3), which functions as a coupled Cl-/HCO3- exchanger, cause CLD. SLC26A3 is a membrane protein predicted to contain 12 transmembrane-spanning alpha-helices and a C-terminal STAS (sulfate transporters and anti-sigma-factor) domain homologous to the bacterial anti-sigma-factor antagonists. The STAS domain is required for SLC26A3 Cl-/HCO3- exchange function and for the activation of cystic fibrosis transmembrane conductance regulator by SLC26A3. Here we investigate the molecular mechanism(s) by which four CLD-causing mutations (Delta Y526/ 7, I544N, I675/6ins, and G702Tins) in the STAS domain lead to disease. In a heterologous mammalian expression system biochemical, immunohistochemical, and ion transport experiments suggest that the four CLD mutations cause SLC26A3 transporter misfolding and/or mistrafficking. Expression studies with the isolated STAS domain suggest that the I675/6ins and G702Tins mutations disrupt the STAS domain directly, whereas limited proteolysis experiments suggest that the Delta Y526/ 7 and I544N mutations affect a later step in the folding and/ or trafficking pathway. The data suggest that these CLD-causing mutations cause disease by at least two distinct molecular mechanisms, both ultimately leading to loss of functional protein at the plasma membrane.
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