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首页> 外文期刊>Journal of Cellular Physiology >TMEM16E (GDD1) Exhibits Protein Instability and Distinct Characteristics in Chloride Channel/Pore Forming Ability
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TMEM16E (GDD1) Exhibits Protein Instability and Distinct Characteristics in Chloride Channel/Pore Forming Ability

机译：蛋白质不稳定和TMEM16E (GDD1)展品不同的氯通道/孔隙的特征形成能力

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TMEM16E/GDD1 has been shown to be responsible for the bone-related late-onset disease gnathodiaphyseal dysplasia (GDD), with the dominant allele (TMEM16Egdd) 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, TMEM16Egdd 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 TMEM16Egdd proteins should be considered for the on-set regulation of their phenotypes in tissues.
机译：TMEM16E / GDD1负责骨晚发性疾病gnathodiaphyseal发育不良(GDD),显性等位基因(TMEM16Egdd)编码一个错义在Cys356突变。TMEM16E隐性等位基因功能丧失也导致晚发性肢带肌营养不良。通过蛋白酶体途径迅速退化,被抑制PI3K救起途径和化学女伴,钠丁酸。比TMEM16E稳定,但显示相似倾向于接受纾困。细胞表面calcium-dependent氯通道(中国)活动,它最初是确定的TMEM16A TMEM16B,由于他们细胞内囊泡分布。造孔TMEM16E领域,共享98年39.8%的相似性与TMEM16A氨基酸,通过域TMEM16A扰乱中国商用飞机有限责任公司活动交换。交换域,模仿守恒的半胱氨酸残留TMEM16A和TMEM16B之间,重组中国商用飞机有限责任公司活动。TMEM16A GDD-causing半胱氨酸突变彻底改变中国商用飞机有限责任公司活动。发现,TMEM16E具有不同的功能除了中国商用飞机有限责任公司和另一个protein-stabilizing向TMEM16E和TMEM16Egdd机械蛋白质应考虑休闲表型的监管组织。

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