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首页> 外文期刊>Biochemistry >Thermal instability of Δf508 cystic fibrosis transmembrane conductance regulator (CFTR) channel function: Protection by single suppressor mutations and inhibiting channel activity
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Thermal instability of Δf508 cystic fibrosis transmembrane conductance regulator (CFTR) channel function: Protection by single suppressor mutations and inhibiting channel activity

机译：ΔF508囊性纤维化跨膜电导调节器（CFTR）通道功能的热不稳定性：通过单一抑制突变保护和抑制信道活动

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摘要

Deletion of Phe508 from cystic fibrosis transmembrane conductance regulator (CFTR) results in a temperature-sensitive folding defect that impairs protein maturation and chloride channel function. Both of these adverse effects, however, can be mitigated to varying extents by second-site suppressor mutations. To better understand the impact of second-site mutations on channel function, we compared the thermal sensitivity of CFTR channels in Xenopus oocytes. CFTR-mediated conductance of oocytes expressing wt or ΔF508 CFTR was stable at 22 °C and increased at 28 °C, a temperature permissive for ΔF508 CFTR expression in mammalian cells. At 37 °C, however, CFTR-mediated conductance was further enhanced, whereas that due to ΔF508 CFTR channels decreased rapidly toward background, a phenomenon referred to here as "thermal inactivation." Thermal inactivation of ΔF508 was mitigated by each of five suppressor mutations, I539T, R553M, G550E, R555K, and R1070W, but each exerted unique effects on the severity of, and recovery from, thermal inactivation. Another mutation, K1250A, known to increase open probability (P _o) of ΔF508 CFTR channels, exacerbated thermal inactivation. Application of potentiators known to increase P _o of ΔF508 CFTR channels at room temperature failed to protect channels from inactivation at 37 °C and one, PG-01, actually exacerbated thermal inactivation. Unstimulated ΔF508CFTR channels or those inhibited by CFTR _(inh)-172 were partially protected from thermal inactivation, suggesting a possible inverse relationship between thermal stability and gating transitions. Thermal stability of channel function and temperature-sensitive maturation of the mutant protein appear to reflect related, but distinct facets of the ΔF508 CFTR conformational defect, both of which must be addressed by effective therapeutic modalities.
机译：从囊性纤维化跨膜电导调节器（CFTR）缺失PHE508导致温度敏感的折叠缺陷，损害蛋白质成熟和氯化物通道功能。然而，这两种不良反应都可以通过第二位点抑制突变减轻到不同的范围。为了更好地了解第二站突变对信道功能的影响，我们比较了卵脓卵母细胞中CFTR通道的热敏性。 CFTR介导的卵母细胞的卵母细胞的电导在22℃下稳定，在28℃下升高，哺乳动物细胞中的ΔF508CFTR表达的温度允许。然而，在37℃下，进一步提高了CFTR介导的电导，而由于ΔF508，CFTR通道朝背景迅速降低，这里称为“热失活”。通过五种抑制突变，I539T，R553M，G550E，R555K和R1070W中的每一种减轻ΔF508的热失活，但每个施加对来自热灭活的严重程度和恢复的独特作用。另一种突变K1250A，已知增加ΔF508CFTR通道的开放概率（P _O），加剧热失存。已知已知的增强剂在室温下增加ΔF508CFTR通道的P _o未能保护通道在37°C和一个PG-01中灭活，实际上加剧了热失活。非刺激的ΔF508CFTR通道或CFTR _（INH）-172抑制的那些部分保护从热灭活，表明热稳定性和门控转变之间的可能逆关系。突变蛋白的通道功能和温度敏感成熟的热稳定性似乎反映了ΔF508CFTR构象缺陷的相关，但是必须通过有效的治疗方式解决。

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  • 来源
    《Biochemistry》 |2012年第25期|共12页
  • 作者

    Liu X.; ODonnell N.; Landstrom A.; Skach W.R.; Dawson D.C.;

  • 作者单位

    Department of Physiology and Pharmacology Oregon Health and Science University Portland OR 97239 United States;

    Department of Physiology and Pharmacology Oregon Health and Science University Portland OR 97239 United States;

    Department of Physiology and Pharmacology Oregon Health and Science University Portland OR 97239 United States;

    Department of Biochemistry and Molecular Biology Oregon Health and Science University Portland OR 97239 United States;

    Department of Physiology and Pharmacology Oregon Health and Science University Portland OR 97239 United States;

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  • 中图分类 生物化学;
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