TMEM16E (GDD1) Exhibits Protein Instability and Distinct Characteristics in Chloride Channel/Pore Forming Ability
| Autor: | Hiroshi Inoue, Nobuyuki Kamata, Chikara Hirono, Shinichi Fujimoto, Kei Tobiume, Mitsuo Itakura, Kuniko Mizuta, Makoto Sugita, Kazumi Kubozono, Ta To Tran |
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| Rok vydání: | 2013 |
| Předmět: |
chemistry.chemical_classification
Mutation Physiology Clinical Biochemistry Intracellular vesicle Sodium butyrate Cell Biology Biology medicine.disease_cause Molecular biology Amino acid Cell biology chemistry.chemical_compound Protein structure chemistry Chloride channel medicine Missense mutation Chemical chaperone |
| Zdroj: | Journal of Cellular Physiology. 229:181-190 |
| ISSN: | 0021-9541 |
| Popis: | TMEM16E/GDD1 has been shown to be responsible for the bone-related late-onset disease gnathodiaphyseal dysplasia (GDD), with the dominant allele (TMEM16E(gdd) ) encoding a missense mutation at Cys356. Additionally, several recessive loss-of-function alleles of TMEM16E also cause late-onset limb girdle muscular dystrophy. In this study, we found that TMEM16E was rapidly degraded via the proteasome pathway, which was rescued by inhibition of the PI3K pathway and by the chemical chaperone, sodium butyrate. Moreover, TMEM16E(gdd) exhibited lower stability than TMEM16E, but showed similar propensity to be rescued. TMEM16E did not exhibit cell surface calcium-dependent chloride channel (CaCC) activity, which was originally identified in TMEM16A and TMEM16B, due to their intracellular vesicle distribution. A putative pore-forming domain of TMEM16E, which shared 39.8% similarity in 98 amino acids with TMEM16A, disrupted CaCC activity of TMEM16A via domain swapping. However, the Thr611Cys mutation in the swapped domain, which mimicked conserved cysteine residues between TMEM16A and TMEM16B, reconstituted CaCC activity. In addition, the GDD-causing cysteine mutation made in TMEM16A drastically altered CaCC activity. Based on these findings, TMEM16E possesses distinct function other than CaCC and another protein-stabilizing machinery toward the TMEM16E and TMEM16E(gdd) proteins should be considered for the on-set regulation of their phenotypes in tissues. |
| Databáze: | OpenAIRE |
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